BENZOIMIDAZOLE, TETRAHYDRO-QUINOXALINE, BENZOTRIAZOLE, DIHYDRO-IMIDAZO[4,5-c] PYRIDINONE AND DIHYDRO-ISOINDOLONE DERIVATIVES

ABSTRACT

This invention relates to compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein A, R 1  to R 3  are as defined in the specification and G is benzoimidazole, quinoxaline, benzotriazole, dihydro-imidazo[4,5-c]pyridine and dihydro-isoindolone group as defined in the specification, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.07105617.0, filed Apr. 4, 2007, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with novel benzoimidazole,tetrahydro-quinoxaline, benzotriazole, dihydro-imidazo[4,5-c]pyridinoneand dihydro-isoindolone derivatives, their manufacture, pharmaceuticalcompositions containing them and their use as medicaments. The activecompounds of the present invention are useful in the prevention and/ortreatment of diabetes mellitus and other disorders.

In particular, the present invention relates to compounds of the generalformula I

and pharmaceutically acceptable salts thereof.

The compounds of formula I possess pharmaceutical activity, inparticular they are modulators of somatostatine receptor activity. Moreparticularly, the compounds are antagonists of the somatostatinereceptor subtype 5 (SSTR5).

All documents relied upon or cited to below are expressly incorporatedherein by reference.

BACKGROUND

Diabetes mellitus is a systemic disease characterized by metabolicdisorders involving insulin, carbohydrates, fats and proteins, anddisorders in the structure and function of blood vessels. The primarysymptom of acute diabetes is hyperglycemia, often accompanied byglucosuria, the presence in urine of large amounts of glucose, andpolyuria, the excretion of large volumes of urine. Additional symptomsarise in chronic diabetes, including degeneration of the walls of bloodvessels. Although many different human organs are affected by thesevascular changes, the eyes and kidneys appear to be the mostsusceptible. As such, long-standing diabetes mellitus, even when treatedwith insulin, is a leading cause of blindness.

There are three recognized types of diabetes mellitus. Type I diabetesor insulin dependent diabetes mellitus (IDDM) is typically of juvenileonset; ketosis develops early in life with much more severe symptoms andhas a near-certain prospect of later vascular involvement. Control ofType I diabetes is difficult and requires exogenous insulinadministration. Type II diabetes or non-insulin dependent diabetesmellitus (NIDDM) is ketosis-resistant, generally develops later in life,is milder and has a more gradual onset. Gestational diabetes is relatedto Type II diabetes and associated with an increased risk of laterdevelopment of that disease. Type III diabetes is malnutrition-relateddiabetes.

NIDDM is a condition that poses a major threat to the health of thecitizens of the western world. NIDDM accounts for over 85% of diabetesincidence worldwide and about 160 million people are suffering fromNIDDM. The incidence is expected to increase considerably within thenext decades, especially in developing countries. NIDDM is associatedwith morbidity and premature mortality resulting from seriouscomplications, e.g., cardiovascular disease (G. C. Weir and J. L. Leahy,Pathogenesis of non-insulin dependent (Type II) diabetes mellitus, inJoslin's Diabetes Mellitus (Eds. C. R. Kahn and G. C. Weir), 13^(th)Edition, 1994, Lea & Febiger, Malvern, Pa., pp. 240-264). NIDDM ischaracterized by both fasting and post-prandial hyperglycemia resultingfrom abnormalities in insulin secretion and insulin action (G. C. Weiret al., vide supra).

The hyperglycemia in patients suffering from NIDDM can usually beinitially treated by dieting, but eventually most NIDDM patients have totake oral antidiabetic agents and/or insulin injections to normalizetheir blood glucose levels. The introduction of orally effectivehypoglycemic agents was an important development in the treatment ofhyperglycemia by lowering blood glucose levels. Currently, the mostwidely used oral antidiabetic agents are the sulfunylureas, which act byincreasing the secretion of insulin from the pancreas (H. E. Lebovitz,Oral antidiabetic agents, in Joslin's Diabetes Mellitus (Eds. C. R. Kahnand G. C. Weir), 13^(th) Edition, 1994, Lea & Febiger, Malvern, Pa., pp.508-529), the biguanides (e.g., metformin) which act on the liver andperiphery by unknown mechanisms (C. J. Bailey, M. R. C. Path and R. C.Turner N. Engl. J. Med. 1996, 334, 574-579) and the thiazolidinediones(e.g., rosiglitazone/Avandia®), which enhance the effects of insulin atperipheral target sites (G. L. Plosker and D. Faulds Drugs 1999, 57,409-438). These existing oral therapies which comprise a wide variety ofbiguanide, sulfonylurea and thiazolidinedione derivatives have been usedclinically as hypoglycemic agents. However, all three classes ofcompound have side effects. The biguanides, for example metformin, areunspecific and in certain cases have been associated with lacticacidosis, and need to be given over a longer period of time, i.e. theyare not suitable for acute administration (C. J. Bailey et al., videsupra). The sulfonylureas, though having good hypoglycemic activity,require great care during use because they frequently cause serioushypoglycemia and are most effective over a period of circa ten years.The thiazolidinediones may cause weight gain and deterioration ofcardiovascular function following chronic administration (G. L. Ploskerand D. Faulds, vide supra) and troglitazone has been associated with theoccurrence of serious hepatic dysfunction.

Thus, there is a significant and rising need for antidiabetic drugs thathave novel mechanisms of action, thereby avoiding side effects producedby known therapies. The hormone somatostatin (SST) is primarily producedin the intestinal tract and in the pancreas. In addition it acts as aneurotransmitter. The hormone is involved through its receptors in theregulation of several other hormones and in immunoregulation. Inparticular, SST suppresses the secretion of insulin by pancreatic βcells and the secretion of glucagon-like peptide 1 (GLP-1) by L cells.GLP-1 in turn is one of the most potent stimulators of insulinproduction and secretion and is a trophic factor for β cells. Inaddition, GLP-1 directly increases peripheral glucose disposal (e.g., D.A. D'Alessio, S. E. Kahn, C. R. Leusner and J. W. Ensinck, J. Clin.Invest. 1994, 93, 2263-2266). β and L cells express SST receptor subtype5 (SSTR5) and agonizing this receptor suppresses insulin and GLP-1secretion in humans and in animal models (e.g., Y. Zambre, Z. Ling,M.-C. Chen, X. Hou, C.-W. Woon, M. Culler, J. H. Taylor, D. H. Coy, C.van Schravendijk, F. Schuit, D. G. Pipeleers and D. L. Eizirik Biochem.Pharmacol. 1999, 57, 1159-1164; S. P. Fagan, A. Azizzadeh, S. Moldovan,M. K. Ray, T. E. Adrian, X. Ding, D. H. Coy and F. C. Brunicardi Surgery1998, 124, 254-258; M. Norman, S. Moldovan, V. Seghers, X.-P. Wang, F.J. DeMayo and F. C. Brunicardi Ann. Surg. 2002, 235, 767-774; T. A.Tirone, M. A. Norman, S. Moldovan, F. J. DeMayo, X.-P. Wang, F. C.Brunicardi Pancreas 2003, 26, e67-73; M. Z. Strowski, M. Köhler, H. Y.Chen, M. E. Trumbauer, Z. Li, D. Szalkowski, S. Gopal-Truter, J. K.Fisher, J. M. Schaeffer, A. D. Blake, B. B. Zhang and H. A. WilkinsonMol. Endocrinol. 2003, 17, 93-106).

Consequently, antagonizing the effect of SST would lead to increasedperipheral glucose disposal and higher plasma insulin concentrations.Additionally, SSTR5 knockout mice demonstrated higher insulinsensitivity than littermates (M. Z. Strowski, M. Köhler et al., videsupra). In patients suffering from impaired glucose tolerance and NIDDMthese combined effects would moderate the dangerous hyperglycemia andaccordingly reduce the risk of tissue damage. If such SSTR5 antagonistsare sufficiently selective over the other four SST receptors, littleinfluence is expected on secretion of other hormones. Particularly,selectivity over SST receptor subtype 2 avoids influences on glucagonsecretion (K. Cejvan, D. H. Coy and S. Efendic Diabetes 2003, 52,1176-1181; M. Z. Strowski, R. M. Parmar, A. D. Blake and J. M. SchaefferEndocrinology 2000, 141, 111-117). Advantageous over establishedtherapies is the dual mechanism of action to increase insulin secretion(directly on pancreatic β cells and indirectly through GLP-1 releasefrom L cells) and to increase glucose disposal, whereby SSTR5antagonists could have the potential to beneficially influence insulinresistance in patients with NIDDM. In summary, SSTR5 antagonists areexpected to beneficially influence NIDDM, the underlying impairedfasting glucose and impaired glucose tolerance, as well as complicationsof long-standing, insufficiently controlled diabetes mellitus.

GLP-1 is known as an endogenous regulator of gastrointestinal motilityand of food intake reducing appetite as shown in laboratory animals,healthy volunteers and patients with NIDDM (E. Näslund, B. Barkeling, N.King, M. Gutniak, J. E. Blundell, J. J. Holst, S. Rössner and P. M.Hellström Int. J. Obes. 1999, 23, 304-311; J.-P. Gutzwiller, B. Göke, J.Drewe, P. Hildebrand, S. Ketterer, D. Handschin, R. Winterhalder, D.Conen and C. Beglinger Gut 1999, 44, 81-88; J.-P. Gutzwiller, J. Drewe,B. Göke, H. Schmidt, B. Rohrer, J. Larcida and C. Beglinger Am. J.Physiol. 1999, 276, R1541-1544; M. D. Turton, D. O'Shea, I. Gunn, S. A.Beak, C. M. Edwards, K. Meeran, S. J. Choi, G. M. Taylor, M. M. Heath,P. D. Lambert, J. P. Wilding, D. M. Smith, M. A. Ghatei, J. Herbert andS. R. Bloom Nature 1996, 379, 69-72; A. Flint, A. Raben, A. Astrup andJ. J. Hoist J. Clin. Invest. 1998, 101, 515-520; M. B. Toft-Nielsen, S.Madsbad and J. J. Holst Diabetes Care 1999, 22, 1137-1143; P. K.Cheikani, A. C. Haver and R. D. Reidelberger Am. J. Physiol. 2005, 288,R1695-R1706; T. Miki, K. Minami, H. Shinozaki, K. Matsumura, A. Saraya,H. Ikeda, Y. Yamada, J. J. Holst and S. Seino Diabetes 2005, 54,1056-1063); thus, elevated GLP-1 will also counteract obesity, a typicalcondition associated with and leading to NIDDM.

GLP-1 further co-localizes with peptide YY (PYY). Thus, PYY couldpotentially also be increased by SSTR5 antagonists (K. Mortensen, L. L.Lundby and C. Orsov Annals N.Y. Acad. Sci. 2000, 921, 469-472). There isevidence that PYY increases satiety, reduces body weight and improvesglycemic control (N. Vrang, A. N. Madsen, C. M. Tang, G. Hansen and P.J. Larsen Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006, 291,R367-R375; A. P. Sileno, G. C. Brandt, B. M. Spain and S. C. Quay Int.J. Obes. Lond. 2006, 30, 68-72; C. J. Small and S. R. Bloom Expert Opin.Investig. Drugs 2005, 14, 647-653). Taken together, SSTR5 antagonistscould have the potential to act on obesity also through PYY.

GLP-1 is co-secreted with GLP-2 that is, consequently, also regulated bySST through SSTR5 (L. Hansen, B. Hartmann, T. Bisgaard, H. Mineo, P. N.Jørgensen and J. J. Holst Am. J. Phys. 2000, 278, E1010-1018). GLP-2 isenterotrophic and beneficial in patients with malabsorption of certainorigins, such as short bowel syndrome (D. G. Burrin, B. Stoll and X.Guan Domest. Anim. Endocrinol. 2003, 24, 103-122; K. V. Haderslev, P. B.Jeppesen, B. Hartmann, J. Thulesen, H. A. Sorensen, J. Graff, B. S.Hansen, F. Tofteng, S. S. Poulsen, J. L. Madsen, J. J. Holst, M. Staunand P. B. Mortensen Scand. J. Gastroenterol. 2002, 37, 392-398; P. B.Jeppesen J. Nutr. 2003, 133, 3721-3724).

Moreover, there is increasing evidence for a role of SST on immune cellsand expression of SSTR5 on activated T lymphocytes (T. Talme, J.Ivanoff, M. Hägglund, R. J. J. van Neerven, A. Ivanoff and K. G.Sundqvist Clin. Exp. Immunol. 2001, 125, 71-79; D. Ferone, P. M. vanHagen, C. Semino, V. A. Dalm, A. Barreca, A. Colao, S. W. J. Lamberts,F. Minuto and L. J. Hofland Dig. Liver Dis. 2004, 36, S68-77; C. E.Ghamrawy, C. Rabourdin-Combe and S. Krantic Peptides 1999, 20, 305-311).Consequently, SSTR5 antagonists could also prove valuable in treatingdiseases characterized by a disturbed immune system, such asinflammatory bowel disease.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound offormula I:

wherein

-   A is —O— or —NH—;-   R¹ is selected from the group consisting of C₂₋₇-alkyl,    C₂₋₇-alkenyl, C₃₋₇-alkinyl, C₃₋₇-cycloalkyl, halogen-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl and benzyl;-   R² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy,    C₁₋₇-alkoxy-C₁₋₇-alkoxy, —O-benzyl, —O—C₃₋₇-cycloalkyl,    unsubstituted phenyl or phenyl substituted by one to three groups    independently selected from C₁₋₇-alkyl, halogen and C₁₋₇-alkoxy,    halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, amino, pyrrolyl,    imidazolyl and —C(O)OR⁴, wherein R⁴ is C₁₋₇-alkyl;-   R³ is hydrogen or (C₁₋₇-alkoxy,-   or R² and R³ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R² and R³ together are    —O—C(CH₃)₂—CH═CH—;-   G is selected from the groups

wherein

-   R⁵ is hydrogen or C₁₋₇-alkyl;-   R⁶, R⁷, R⁸ and R⁹ are —COOH;-   R¹⁰ is hydrogen or C₁₋₇-alkoxy;    and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of compounds according to formula I, comprising thesteps of:

-   a) reacting a piperidine of the formula

wherein G is as defined above, with an aldehyde of the formula

wherein A and R¹ to R³ are as defined above, by employing a reducingagent to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively,

-   b) alkylating a piperidine of the formula

wherein G is as defined above, with a compound of the formula

wherein A and R¹ to R³ are as defined above and X is a leaving group,under basic conditions to obtain a compound or formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively,

-   c) reacting a compound of the general formula

wherein G is as defined above, with a compound of the formula

wherein A and R¹ to R³ are as defined above, in the presence of atrialkylphosphine and a diazo-compound to obtain a compound of theformula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I as well as apharmaceutically acceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, provided is amethod for the treatment and/or prevention of diseases which areassociated with the modulation of SST receptors subtype 5, comprisingthe step of administering a therapeutically effective amount of acompound according to formula I to a human being or animal in needthereof.

DETAILED DESCRIPTION

The present invention provides for selective, directly acting SSTR5antagonists. Such antagonists are useful as therapeutically activesubstances, particularly in the treatment and/or prevention of diseaseswhich are associated with the modulation of SST receptors subtype 5.

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms,preferably one to sixteen carbon atoms, more preferably one to tencarbon atoms.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms, preferably a straight or branched-chain alkyl group with 1to 4 carbon atoms. Examples of straight-chain and branched C₁-C₇ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomericheptyls, preferably methyl, ethyl and isopropyl, and most preferred thegroups specifically exemplified herein.

The term “lower alkenyl” or “C₂₋₇-alkenyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 7, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.A preferred example is 2-propenyl (allyl).

The term “lower alkinyl” or “C₃₋₇-alkinyl” signifies a straight-chain orbranched hydrocarbon residue comprising a triple bond and up to 7,preferably up to 6, particularly preferred up to 4 carbon atoms.Examples of alkinyl groups are 2-propinyl, 2-butinyl and 3-butinyl. Apreferred example is 2-propinyl.

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” refers to a monovalentcarbocyclic radical of three to seven, preferably three to five carbonatoms. This term is further exemplified by radicals such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with cyclobutylbeing especially preferred.

The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. Theterm “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—, whereinR′ is lower alkyl and the term “lower alkyl” has the previously givensignificance. Examples of lower alkoxy groups are e.g., methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy,preferably methoxy and ethoxy and most preferred the groups specificallyexemplified herein.

The term “lower alkoxyalkyl” or “C₁₋₇-alkoxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by an alkoxy group as definedabove. Among the preferred lower alkoxyalkyl groups are methoxymethyl,methoxyethyl and ethoxymethyl.

The term “lower alkoxyalkoxy” or “C₁₋₇-alkoxy-C₁₋₇-alkoxy” refers tolower alkoxy groups as defined above wherein at least one of thehydrogen atoms of the lower alkoxy group is replaced by an alkoxy groupas defined above. Among the preferred lower alkoxyalkoxy groups are2-methoxy-ethoxy and 3-methoxy-propoxy.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to loweralklyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,difluoroethyl, fluoromethyl and chloromethyl, with trifluoromethyl anddifluoroethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy,fluoromethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Examples oflower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl, but alsogroups having two hydroxy groups such as2-hydroxy-1-hydroxymethyl-ethyl.

The term “lower hydroxyalkoxy” or “hydroxy-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a hydroxy group. Examplesof lower hydroxyalkoxy groups are hydroxymethoxy or hydroxyethoxy.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g., hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place, e.g., as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The term“pharmaceutically acceptable salts” also includes physiologicallyacceptable solvates.

¢Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In detail, the present invention relates to compounds of the generalformula I

wherein

-   A is —O— or —NH—;-   R¹ is selected from the group consisting of C₂₋₇-alkyl,    C₂₋₇-alkenyl, C₁₋₇-alkinyl, C₃₋₇-cycloalkyl, halogen-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl and benzyl;-   R² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy,    C₁₋₇-alkoxy-C₁₋₇-alkoxy, —O-benzyl, —O—C₃₋₇-cycloalkyl,    unsubstituted phenyl or phenyl substituted by one to three groups    independently selected from C₁₋₇-alkyl, halogen and C₁₋₇-alkoxy,    halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, amino, pyrrolyl,    imidazolyl and —C(O)OR⁴, wherein R⁵ is C₁₋₇-alkyl;-   R³ is hydrogen or C₁₋₇-alkoxy;-   or R² and R³ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R² and R³ together are    —O—C(CH₃)₂—CH═CH—;-   G is selected from the groups

wherein

-   R⁵ is hydrogen or C₁₋₇-alkyl;-   R⁶, R⁷, R⁸ and R⁹ are —COOH;-   R¹⁰ is hydrogen or C₁₋₇-alkoxy;    and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I of the present invention are alsothose, wherein A is O.

A further group of compounds of formula I are those, wherein A is NH.

Also preferred are compounds of formula I according to the invention,wherein R¹ is selected from the group consisting of C₂₋₇-alkyl,C₂₋₇-alkenyl, C₃₋₇-alkinyl, C₃₋₇-cycloalkyl and halogen-C₁₋₇-alkyl.Especially preferred are those compounds of formula I, wherein R² isselected from the group consisting of ethyl, propyl, isopropyl, allyl,2-fluoroethyl, butyl, isobutyl, cyclopentyl and 2-propynyl, with thosecompounds, wherein R² is ethyl or isopropyl, being most preferred.

Further preferred compounds of formula I according to the presentinvention are those, wherein R² is selected from the group consisting ofhydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, —O-benzyl,—O—C₃₋₇-cycloalkyl, unsubstituted phenyl or phenyl substituted by one tothree groups independently selected from C₁₋₇-alkyl, halogen andC₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkoxy, amino, pyrrolyl, imidazolyland —C(O)OR⁴, wherein R⁴ is C₁₋₇-alkyl.

More preferred are those compounds of formula I, wherein R² is selectedfrom the group consisting of group consisting of hydrogen, C₁₋₇-alkoxy,halogen, halogen-C₁₋₇-alkoxy, pyrrolyl, phenyl substituted by halogenand —C(O)OR⁴, wherein R⁴ is C₁₋₇-alkyl, with those compounds, wherein R²is halogen, being especially preferred. Most preferably, R² is chloro.

Furthermore, compounds of formula I of the present invention arepreferred, wherein R³ is hydrogen or C₁₋₇-alkoxy.

Another group of preferred compounds of formula I according to thepresent invention are those, wherein R² and R³ are bonded to each otherto form a ring together with the carbon atoms they are attached to andR² and R³ together are —O—C(CH₃)₂—CH═CH—. These are compounds of theformula Ix:

Preferred are further compounds of formula I according to the presentinvention, wherein G is

and wherein R⁵ is hydrogen or C₁₋₇-alkyl and R⁶ is —COOH.

More preferably, R⁵ is methyl.

Furthermore, compounds of formula I according to the invention arepreferred, wherein G is

and wherein R⁷ is —COOH.

Also preferred are compounds of formula I according to the presentinvention, wherein G is

and wherein R⁸ is —COOH.

Further preferred are compounds of formula I according to the invention,wherein G is

and wherein R⁹ is —COOH.

Also preferred are compounds of formula I according to the invention,wherein G is

Furthermore, compounds of formula I according to the invention arepreferred, wherein G is

and wherein R¹⁰ is hydrogen or C₁₋₇-alkoxy.

Especially preferred are those compounds of formula I, wherein R¹⁰ ismethoxy.

Examples of preferred compounds of formula I are the following:

-   1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-isopropoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid-   1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-isopropoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-methoxy-3-prop-2-ynyloxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,-   2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,-   2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,-   2-[1-(2-ethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,-   2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,-   2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,-   2-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,-   2-[1-(2-ethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,    and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds of formula I of thepresent invention:

-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic    acid,-   1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic    acid-   1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,-   2-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises

-   a) reacting a piperidine of the formula

wherein G is as defined herein before, with an aldehyde of the formula

wherein A and R¹ to R³ are as defined herein before, by employing areducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively,

-   b) alkylating a piperidine of the formula

wherein G is as defined herein before, with a compound of the formula

wherein A and R¹ to R³ are as defined herein before and X is a leavinggroup, under basic conditions to obtain a compound, or formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively,

-   c) reacting a compound of the general formula

wherein G is as defined herein before, with a compound of the formula

wherein A and R¹ to R³ are as defined herein before, in the presence ofa trialkylphosphine and a diazo-compound to obtain a compound of theformula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt.

The invention further relates to compounds of formula I as definedabove, when manufactured according to a process as defined above.

Suitable reducing agents are preferably selected from the groupconsisting of pyridine-BH₃ complex, NaBH(OAc)₃ and NaCNBH₃. The reactioncan be carried out under acidic conditions by using an acid such asacetic acid or formic acid or a Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) orunder buffered conditions (e.g., in the presence of acetic acid and atertiary amine like N-ethyldiisopropylamine or triethylamine) in asuitable solvent such as dichloromethane, dichloroethane, ethanol orisopropanol (or mixtures thereof) at ambient or elevated temperaturesusing conventional heating or heating by microwave irradiation.

Suitable leaving groups X are halides, mesylates or tosylates oralcohols containing another leaving group. Preferred leaving groups areselected from the group consisting of iodide, bromide, methanesulfonateand chloride.

Suitable trialkylphosphines are tributylphosphine andtriphenylphosphine. Preferred diazo compounds are diethylazodicarboxalate (DEAD), diisopropyl azodicarboxylate (DIAD) ordi-tert-butyl azodicarboxylate.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prevention ofdiseases which are associated with the modulation of SST receptorssubtype 5.

Diseases which are associated with the modulation of SST receptorssubtype 5 are such diseases as diabetes mellitus, particularly type IIdiabetes mellitus, impaired fasting glucose, impaired glucose tolerance,micro- and macrovascular diabetic complications, post transplantationdiabetes mellitus in patients having type I diabetes mellitus,gestational diabetes, obesity, inflammatory bowel diseases such asCrohn's disease or ulcerative colitis, malabsorption, autoimmunediseases such as rheumatoid arthritis, osteoarthritis, psoriasis andother skin disorder, and immunodeficiences. Microvascular diabeticcomplications include diabetic nephropathy and diabetic retinopathy,whereas macrovascular diabetes-associated complications lead to anincreased risk for myocardial infarction, stroke and limb amputations.

The use as medicament for the treatment and/or prevention of diabetesmellitus, particularly type II diabetes mellitus, impaired fastingglucose or impaired glucose tolerance is preferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which areassociated with the modulation of SST receptors subtype 5.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are associated with themodulation of SST receptors subtype 5, which method comprisesadministering a compound of formula I to a human or animal. The methodfor the treatment and/or prevention of diabetes mellitus, particularlytype II diabetes mellitus, impaired fasting glucose or impaired glucosetolerance, is most preferred.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prevention of diseases which are associatedwith the modulation of SST receptors subtype 5.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprevention of diseases which are associated with the modulation of SSTreceptors subtype 5. Preferred examples of such diseases are diabetesmellitus, particularly type II diabetes mellitus, impaired fastingglucose or impaired glucose tolerance.

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps arestandard reactions and are known to a person skilled in the art.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the text or in the examples, or by methods known inthe art.

The synthesis of compounds with the general structure I, particularlycompounds according to formula Ia to If, are described in Schemes 1 to6.

The synthesis of compounds according to formula Ia can be accomplishedaccording to Scheme 1. Starting from appropriately substitutedpara-fluoro-benzoic acids like 1 nitration with potassium nitrate inconc. sulfuric acid, preferably at rt, provides nitro-derivatives 2(Scheme 1, step a). Introduction of a suitable carboxylic acidprotection group (see Protective Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) Edition, 1999, Wiley-Interscience) suchas an allyl ester gives then access to derivatives 3 (Scheme 1, step b).The esterification can be conducted using an allylhalide (e.g.,allylbromide) in the presence of a base like potassium or sodiumcarbonate in a suitable solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF) or dioxane (or mixtures thereof) at ambient orelevated temperatures using conventional heating or heating by microwaveirradiation. Appropriately protected nitro-fluoro-benzoic acids 3undergo nucleophilic aromatic substitution (SN_(Ar)) with4-amino-piperidines 4 in a solvent such as DMF and the presence of asuitable tertiary amine base (e.g., triethylamine,N-ethyldiisopropylamine) at preferably elevated temperatures to provideintermediates 5 (Scheme 1, step c). Reduction of the nitro group incompound 5 yielding the corresponding aniline derivative 6 can beeffected in a manner which will be familiar to any person skilled in theart such as reduction with Zn in the presence of a mild acid at roomtemperature or under healing to reflux (Scheme 1, step d). Formation ofthe benzoimidazole derivative 7 can be achieved upon ring closure ofaniline 6 with acetaldehyde in the presence of copper(II) acetate in apolar protic solvent such as ethanol and by heating to reflux. Thealkyloxycarbonyl protecting group present in compounds 7 can be removed,using e.g., 48% aqueous hydrogen bromide or 37% aqueous hydrochloricacid as reagent preferably at elevated temperatures to cleave an ethylcarbamate or using trifluoroacetic acid or hydrochloric acid in asolvent like dichloromethane (DCM), dioxane or THF preferable at roomtemperature to remove a tert-butyloxycarbonyl (BOC)-protective group(see Protective Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) Edition, 1999, Wiley-Interscience), yielding piperidines offormula 8 (Scheme 1, step f).

Reductive N-alkylation of free piperidines 8 with aldehydes 9 in thepresence of a reducing agent such as pyridine-BH₃ complex, NaBH(OAc)₃ orNaCNBH₃ under acidic conditions (e.g., acetic acid, formic acid), byusing a Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) or under bufferedconditions, e.g., in the presence of acetic acid and a tertiary aminelike N-ethyldiisopropylamine or triethylamine, in a suitable solventsuch as dichloromethane (DCM), dichloroethane, ethanol or isopropanol(or mixtures thereof) at ambient or elevated temperatures usingconventional heating or heating by microwave irradiation provides targetstructures Ia (Scheme 1, step g). In the coupling step piperidines offormula 8 may thereby be used either as salt, e.g., hydrochloride orhydrobromide, or as the corresponding free amine.

Target compounds of formula Ia might also be manufactured by directalkylation of piperidines 8 with suitable halides, mesylates, tosylatesor alcohols transformed into any other suitable leaving group X ofgeneral structure 10 in a solvent such as DMF, dichloromethane,dichloroethane or acetone at ambient or elevated temperatures usingconventional heating or heating by microwave irradiation with theaddition of a suitable tertiary amine base (e.g., triethylamine,N-ethyldiisopropylamine) or an inorganic base (e.g., Cs₂CO₃, K₂CO₃) orby analogous alkylation reactions (Scheme 1, step h). Alternativelytarget structures of formula Ia might be accessible by Mitsunobureaction (D. L. Hughes, The Mitsunobu Reaction, in Organic Reactions,Volume 42, 1992, John Wiley & Sons, New York; pp. 335-656) applyingalcohols 11 activated by a mixture of a phosphine like atrialkylphosphine such as tributylphosphine ((n-Bu)₃P),triphenylphosphine (Ph₃P) and the like and a diazo-compound like diethylazodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) ordi-tert-butyl azodicarboxylate and the like in a solvent commonly usedfor such transformations like THF, toluene, DCM and the like (Scheme 1,step h). There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve the reagents, at leastto some extent. The reaction can take place over a wide range oftemperatures ranging from ambient temperature to the reflux temperatureof the solvent employed.

Target structures Ib are accessible via benzoimidazoles 12 which can besynthesized by ring closure reaction of aniline 6 with a suitablyactivated carbonyl source such as triphosgene in the presence of atertiary amine base (e.g., triethylamine, N-ethyldiisopropylamine) in aninert solvent like toluene, DCM or the like (Scheme 2, step a). Thereaction may be conducted at ambient or elevated temperature, wherebyhigher temperatures might be preferred. Removal of the alkyloxycarbonylprotecting group in 12 under strong acid catalysis (Scheme 2, step b)and reductive alkylation with aldehydes 9 or direct alkylation withintermediates 10 under conditions as previously discussed providesaccess to target compounds Ib (Scheme 2, step c). Alternatively, targetcompounds of formula Ib might also be manufactured by direct alkylationof piperidines 13 with suitable halides, mesylates, tosylates oralcohols transformed into any other suitable leaving group X of generalstructure 10 or by analogous alkylation reactions. Target structures offormula Ib might also be accessible by Mitsunobu reaction (D. L. Hughes,The Mitsunobu Reaction, in Organic Reactions, Volume 42, 1992, JohnWiley & Sons, New York; pp. 335-656) applying alcohols 11 activated by amixture of a phosphine like a trialkylphosphine such astributylphosphine ((n-Bu)₃P), triphenylphosphine (Ph₃P) and the like anda diazo-compound like diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) or di-tert-butyl azodicarboxylate and the likein a solvent commonly used for such transformations like THF, toluene,DCM and the like.

Target compounds of general structures Ic can be accomplished by amidebond formation of aniline 6 with a bromoacetyl halide, preferentiallybromoacetyl chloride, in the presence of a tertiary amine base (e.g.,triethylamine, N-ethyldiisopropylamine) in a inert solvent like DCM ortoluene and the like at room or elevated temperature (Scheme 3, step a).Ring closure reaction of amide intermediate 14 to tetrahydro-quinoxaline15 is then achieved by conventional heating or heating by microwaveirradiation in the presence of a tertiary amine base such asN-ethyldiisopropylamine (Scheme 3, step b). Removal of thealkyloxycarbonyl protecting group in 15 under strong acid catalysis(Scheme 3, step c) and reductive alkylation with aldehydes 9 or direktalkylation with intermediates 10 under conditions as previouslydiscussed provides access to target compounds Ic (Scheme 3, step d).Target structures of formula Ic might also be accessible by Mitsunobureaction (D. L. Hughes, The Mitsunobu Reaction, in Organic Reactions,Volume 42, 1992, John Wiley & Sons, New York; pp. 335-656) applyingalcohols 11 activated by a mixture of a phosphine like atrialkylphosphine such as tributylphosphine ((n-Bu)₃P),triphenylphosphine (Ph₃P) and the like and a diazo-compound like diethylazodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD)) ordi-tert-butyl azodicarboxylate and the like in a solvent commonly usedfor such transfomations like THF, toluene, DCM and the like.

Target compounds of general structures Id can be prepared bydiazotization of aniline 6 with sodium nitrite under strongly acidicreaction (e.g., hydrochloric acid) conditions (Scheme 4, step a). The insitu formed diazonium cation spontaneously ring closes to benzotriazoleintermediate 17. Removal of the alkyloxycarbonyl protecting group in 17under strong acid catalysis (Scheme 4, step b) and reductive alkylationwith aldehydes 9 or direkt alkylation with intermediates 10 underconditions as previously discussed provides access to target compoundsId (Scheme 4, step c). Alternatively, target compounds of formula Idmight also be manufactured by Mitsunobu reaction (D. L. Hughes, TheMitsunobu Reaction, in Organic Reactions, Volume 42, 1992, John Wiley &Sons, New York; pp. 335-656) with alcohols 11.

The synthesis of target structures Ie commences with nucleophilicaromatic substitution (SN_(Ar)) of appropriately substituted4-chloro-3-nitro-pyridines 19 with 4-amino-piperidines 4 in a solventsuch as DMF and the presence of a suitable tertiary amine base (e.g.,triethylamine, N-ethyldiisopropylamine) at ambient or elevatedtemperatures (Scheme 5, step a). The nitro group of intermediates 20 canbe reduced to the corresponding aniline derivative 21 by reduction withhydrogen under palladium on carbon catalysis at ambient or slightlyelevated pressure using a low boiling alcohol such as methanol orethanol (Scheme 5, step b). Formation of the imidazo[4,5-c]pyridinederivative 22 can be achieved by treatment of aniline 21 with triethylorthoformate under acid catalysis (e.g., toluene-4-sulfonic acid) in aninert solvent such as toluene at ambient or elevated temperature (Scheme5, step c). Preferentially the reaction is conducted at the refluxtemperature of toluene.

Oxidation of compound 22 to the pyridine oxide 23 is achieved bytreatment with 3-chloro-perbenzoic acid at room or elevated temperaturein a solvent such as DCM (Scheme 5, step d). Oxygen migration of theN-oxide 23 to imidazo[4,5-c]pyridinone 24 is induced by heating toreflux in the presence of acetic anhydride (Scheme 5, step e). Under thesame reaction conditions the tert-butyloxycarbonyl (BOC)-protectivegroup in 23 is exchanged to the corresponding acetamide which can betaken off under strong acid catalysis, preferably at elevatedtemperatures (Scheme 5, step f). Reductive alkylation of piperidine 25with aldehydes 9 or direkt alkylation with intermediates 10 underconditions as previously discussed provides direct access to targetcompounds Ie (Scheme 5, step g). Alternatively, target compounds offormula Ie might also be manufactured by Mitsunobu reaction (D. L.Hughes, The Mitsunobu Reaction, in Organic Reactions, Volume 42, 1992,John Wiley & Sons, New York; pp. 335-656) with alcohols 11 as shownbefore.

Target compounds of general structures If can be prepared starting withradical bromination of the methyl group in 26 by, e. g., heating in CCl₁in the presence of N-bromosuccinimide and dibenzoyl peroxide asinitiator (Scheme 6, step a). Ensuing ring closure reaction ofintermediate 27 with suitably protected 4-aminopiperidine 4 to2,3-dihydro-isoindol-1-one 28 is then achieved by reacting them atambient temperature or slight heating in the presence of a tertiaryamine base such as triethylamine or N-ethyldiisopropylamine (Scheme 6,step b). Removal of the alkyloxycarbonyl protecting group in 28 understrong acid catalysis to give piperidine 29 (Scheme 6, step c) andreductive alkylation with aldehydes 9 or direkt alkylation withintermediates 10 under conditions as previously discussed providesaccess to target compounds If (Scheme 6, step d).

Synthesis of Aldehyde Intermediates

The requisite aldehyde partners are either commercially available or canbe derived by alkylation with alkyl halides, alkyl mesylates, alklyltosylates or alcohols containing any other suitable leaving group in apolar solvent such as DMF (N,N-dimethylformamide) or acetone and asuitable base (e.g., Cs₂CO₃, K₂CO₃) at room temperature or elevatedtemperatures, by Mitsunobu reaction with alcohols activated by a mixtureof triphenylphosphine and diethyl azadicarboxylate, or by analogousalkylation of the phenolic carboxylic esters or acids of formula 30(Scheme 7, step a). Reduction of the esters of formula 31 by a suitablereducing agent (e.g., diisobutylaluminum hydride at low temperature orwith LiAlH₄ at low, elevated or ambient temperature) in a solvent suchas THF provides the corresponding benzylalcohols of formula 32 (Scheme7, step b), which can then be oxidized to the aldehydes of formula 9,preferably with activated MnO₂ as oxidant in DCM (Scheme 7, step c).

Alternatively the introduction of the side-chain can be accomplished bydirect alkylation (sequential for unsymmetrical compounds) of thephenolic benzaldehydes of formula 33 providing the desired compounds offormula 9 directly (Scheme 7, step d). A further well-established routetowards the synthesis of benzaldehydes of formula 9 consists in thereduction of the corresponding benzonitriles of formula 34 by a suitablereducing agent such as diisobutylaluminum hydride at low temperature ina non-protic polar solvent (e.g., THF; Scheme 7, step e).

Additional syntheses of aldehydes of formula 11 are described in theexamples.

As described hereinbefore, it has been found that the compounds offormula I possess pharmaceutical activity, in particular they aremodulators of somatostatin receptor activity. More particularly, thecompounds of the present invention have been found to be antagonists ofthe somatostatin receptor subtype 5 (SSTR5).

The following tests were carried out in order to determine the activityof the compounds of formula I.

A CHO cell line stably transfected with a plasmid encoding the humansubtype 5 somatostatin receptor (GenBank accession number D16827) wasobtained from Euroscreen. Cells were cultured and used for binding andfunctional assays.

Membranes of these cells were prepared by sonication in the presence ofprotease inhibitors and subsequent fractionating centrifugation. Theprotein concentration in the membrane preparation was determined using acommercial kit (BCA kit, Pierce, USA). Membranes were stored at −80° C.until use. After thawing membranes were diluted in assay buffer (50 mMTris-HCl at pH 7.4, 5 mM MgCl₂ and 0.20% BSA) and subjected to douncehomogenization.

For binding studies, 0.1 mL membrane suspension, corresponding toapproximately 6×10⁻¹⁵ mol receptor, was incubated for 1 h at rt with0.05 nM ¹²⁵I-labeled tracer (11-Tyr somatostatin-14, Perkin-Elmer) andeither test compounds in varying concentrations or, for thedetermination of non-specific binding, 0.001 mM non-labeledsomatostatin-14. The incubation was stopped by filtration through GF/Bglassfiber filters and washing with ice-cold wash buffer (50 mM Tris-HClat pH 7.4). The bound radioactivity was measured after application of ascintillation cocktail (Microscint 40) and expressed as disintegrationsper minute (dpm).

The receptor concentration was determined in a prior saturationexperiment where a fixed, arbitrary amount of membranes was incubatedwith a concentration range of radio-labeled tracer. This allowsestimating the total number of specific binding sites per amount ofprotein (i.e., B_(max)), typically between 1 and 5 pmol/mg.

The concentration of the test compound required to result in halfmaximal inhibition of binding of the radio-labeled tracer (IC₅₀) wasestimated from a concentration-versus-dpm graph. The binding affinity(K_(i)) was calculated from the IC₅₀ by applying the Cheng-Prussoffequation for single binding sites.

For functional experiments, 50'000 cells were incubated in Krebs RingerHEPES buffer (115 mM NaCl, 4.7 mM KCl, 2.56 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2mM MgSO₄, 20 mM NaHCO₃ and 16 mM HEPES, adjusted to pH 7.4) supplementedwith 1 mM IBMX and 0.1% BSA, then stimulated with 0.004 mM forskolin.Simultaneously with forskolin, test compounds in varying concentrationswere applied. Cells were then incubated for 20 minutes at 37° C. and 5%CO₂. Subsequently, cells were lysed and cAMP concentration measuredusing a fluorescence-based commercial kit according to the manufacturer(HitHunter cAMP, DiscoverX).

The concentration of the test compound to induce a half maximal effect(i.e., EC₅₀) as well as the efficacy as compared to 0.15 nMsomatostatin-14 were determined from concentration-versus-fluorescence(arbitrary units) graphs. For the determination of potential antagonism,0.15 nM somatostatin-14 was applied together with the test compounds andthe concentration of the test compounds to half maximally reverse theeffect of somatostatin-14 (i.e., IC₅₀) were deduced fromconcentration-versus-fluorescence graphs.

The compounds of the present invention exhibit in a radioligandreplacement assay K_(i) values of 0.1 nM to 10 μM, preferably K_(i)values of 0.1 nM to 500 nM and more preferably 0.1 nM to 100 nM for thehuman subtype 5 somatostatin receptor. The following table showsmeasured values for selected compounds of the present invention.

SSTR5 K_(i) (nmol/l) Example 13 0.108 Example 51 0.653 Example 84 0.005

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g., in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.,in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g., in theform of suppositories, parenterally, e.g., in the form of injectionsolutions or infusion solutions, or topically, e.g., in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable, into a galenical administration form together with suitable,non-toxic, inert, therapeutically compatible solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula I.

The present invention will be further explained by reference to thefollowing illustrative examples. They are, however, not intended tolimit its scope in any manner.

EXAMPLES Abbreviations

Ar=argon, Celite=filtration aid, DMF=N,N-dimethylformamide,DMSO=dimethyl sulfoxide, EI=electron impact (ionization), HPLC=highperformance liquid chromatography, Hyflo Super Cel®=filtration aid(Fluka), ISP=ion spray positive (mode), NMR=nuclear magnetic resonance,MPLC=medium pressure liquid chromatography, MS=mass spectrum,P=protecting group, R=any group, rt=room temperature,THF=tetrahydrofuran, X=halogen.

Example 11-[1-(3-Ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid Step 1: 4-Fluoro-3-nitro-benzoic acid

To a cold solution of 4-fluorobenzoic acid (50.0 g, 0.36 mol, 1.0 equiv)in concentrated H₂SO₄ (180 ml) was added portionwise potassium nitrate(39.7 g, 0.39 mol, 1.1 equiv). The reaction mixture was stirredovernight at rt and then poured on crushed ice (800 g) with constantstirring. The resulting mixture was kept overnight at rt, filtered andwashed thoroughly with water, and finally dried by making an azeotropewith toluene to yield 59.5 g (90%) of the title compound as a lightyellow solid. ¹H NMR (400 MHz, DMSO): δ 7.69-7.74 (m, 1H), 8.29-8.32 (m,1H), 8.56 (d, J=7.2 Hz, 1H), 13.75 (br s, 1H).

Step 2: 4-Fluoro-3-nitro-benzoic acid allyl ester

To a mechanically stirred solution of 4-fluoro-3-nitro-benzoic acid(113.0 g, 0.61 mol, 1.0 equiv) in DMF (770 ml) was added portionwisepotassium carbonate (168.7 g, 1.22 mol, 2.0 equiv). Allyl bromide (110.8g, 0.92 mol, 1.5 equiv) was added to the reaction mixture and stirringcontinued at rt overnight. The reaction mixture was filtered, thefiltrate poured into water (4 L), kept for 2 h and then extracted withethyl acetate (3×1 L). The organic layer was washed with water, driedover Na₂SO₄ and concentrated by evaporation under reduced pressure. Theresidue was purified with silica column chromatography eluting with agradient of hexane/ethyl acetate (100:0→98:2) to obtain 114.1 g (83%) ofthe title compound. ¹H NMR (400 MHz, DMSO): δ 4.86 (d, J=5.4 Hz, 2H),5.30 (d, J=10.6 Hz, 1H), 5.43 (d, J=17.2, 1H), 6.01-6.10 (m, 1H),7.73-7.78 (m, 1H), 8.34-8.37 (m, 1H), 8.60 (d, J=7.2 Hz, 1H).

Step 3:4-(4-allyloxycarbonyl-2-nitro-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-fluoro-3-nitro-benzoic acid allyl ester (84.3 g, 0.37mol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butylester (75.0 g, 0.37 mol, 1.0 equiv; commercially available) in DMF (500mL) was added N-ethyldiisopropylamine (111.3 g, 0.86 mol, 2.3 equiv) andthe reaction mixture heated at 70° C. for 6 h. The reaction mixture wascooled, poured into water (2 L) and the resulting mixture stirred at rtfor 1 h. The precipitate was filtered, washed with water and hexane andfinally dried over MgSO₄ to obtain 129.1 g (85%) of the title compound.¹H NMR (400 MHz, DMSO): δ 1.46 (s, 9H), 1.46-1.56 (m, 2H), 1.92-1.98 (m,2H), 2.90-2.98 (m, 2H), 3.88-3.95 (m, 3H), 4.78 (d, J=5.2 Hz, 2H), 5.27(d, J=10.4 Hz, 1H), 5.38 (d, J=17.3 Hz, 1H), 6.00-6.06 (m, 1H), 7.29 (d,J=9.2 Hz, 1H), 7.99 (dd, J=9.2 Hz, J=1.6 Hz, 1H), 8.24 (d, J=7.8 Hz,1H), 8.64 (s, 1H).

Step 4:4-(4-Allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a stirred suspension of4-(4-allyloxycarbonyl-2-nitro-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (20.0 g, 49.33 mmol, 1.0 equiv) and Zn (23.22 g) 0.36mol, 7.2 equiv) was added a sat. solution of NH₄Cl (7.91 g, 0.15 mol,3.0 equiv) and the reaction mixture heated to reflux. After 45 min, thereaction was cooled, filtered through Celite and concentrated byevaporation under reduced pressure. The filtrate was diluted with waterand extracted with dichloromethane (3×200 mL). The combined organicfractions were washed with water, dried over Na₂SO₄ and concentrated byevaporation under reduced pressure. The brownish solid material wasfurther washed with a mixture of hexane/ethyl acetate (98:2) to yield15.7 g (85%) of the title product. ¹H NMR (400 MHz, DMSO): δ 1.24-1.33(m, 2H), 1.46 (s, 9H), 1.90-1.94 (m, 2H), 2.88-2.94 (m, 2H), 3.53-3.55(m, 1H), 3.88-3.95 (m, 2H), 4.68 (d, J=5.2 Hz, 2H), 4.79 (s, 2H), 5.01(d, J=7.5, 2H), 5.23 (d, J=10.4 Hz, 1H), 5.34 (d, J=17.3 Hz, 1H),6.00-6.06 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 7.21 (m, 2H).

Step 5:1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-2-methyl-1H-benzoimidazole-5-carboxylicacid allyl ester

To a stirred solution of4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (15.0 g, 39.95 mmol, 1.0 equiv) in ethanol (250 mL)were added copper(II) acetate (14.51 g, 79.90 mmol, 2.0 equiv) andacetaldehyde (44.1 mL, 0.20 mol, 5.0 equiv; 20% solution in water) andthe reaction mixture heated to refluxe for 36 h. The solvent wasevaporated, the residue diluted with water and extracted with ethylacetate. The combined organic fractions were washed with water and asat. solution of NaCl, dried over Na₂SO₄, concentrated by evaporationunder reduced pressure and purified with silica column chromatographyeluting with a gradient of hexane/ethyl acetate (3:7→1:9) to obtain 7.2g (45%) of the title compound as a brown solid. ¹H NMR (400 MHz, DMSO):δ 1.46 (s, 9H), 1.88-1.91 (m, 2H), 2.14-2.20 (m, 2H), 2.63 (s, 3H), 2.97(br s, 2H), 4.13-4.15 (m, 2H), 4.58 (t, J=11.5 Hz, 1H), 4.81 (d, J=4.6Hz, 2H), 5.28 (d, J=10.4 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 6.03-6.10 (m,1H), 7.68 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 8.14 (s, 1H). MS(ISP): 400.3 [M+H]⁺.

Step 6: 2-Methyl-1-piperidin-4-yl-1H-benzoimidazole-5-carboxylic acidallyl ester dihydrochloride (Intermediate A1)

A solution of1-(1-tert-butoxycarbonyl-piperidin-4-yl)-2-methyl-1H-benzoimidazole-5-carboxylicacid allyl ester (1.60 g, 4.01 mmol) in dioxane (20 mL) and 4 M HCl indioxane (20 mL) was stirred at rt for 2 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 300.4 [M+H]⁺.

Step 7:1-[1-(3-Ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid

To a solution of2-methyl-1-piperidin-4-yl-1H-benzoimidazole-5-carboxylic acid allylester dihydrochloride (55.8 mg, 0.15 mmol, 1.0 equiv; intermediate A1)in methanol (0.8 mL) and water (0.4 mL) was added a solution of 10 MNaOH (60 μL), acetic acid (86 μL, 90.3 mg, 1.50 mmol, 10 equiv),3-ethoxy-4-fluoro-benzaldehyde (30.3 mg, 0.18 mmol, 1.2 equiv;intermediate B1, vide infra) and sodium cyanoborohydride (47.1 mg, 0.75mmol, 5.0 equiv), dissolved in ethanol (0.5 mL). The reaction mixturewas stirred at 70° C. overnight. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 13.4 mg (22%) of thetitle compound. MS (ISP): 412.3 [M+H]⁺.

The benzoimidazole, tetrahydro-quinoxaline, benzotriazole anddihydro-imidazo[4,5-c]pyridinone intermediates A2 to A5 were prepared asdescribed below. Synthesis of Benzoimidazole, Tetrahydro-quinoxaline,Benzotriazole and Dihydro-imidazo[4,5-c]pyridinone Intermediates A2 toA5 to be used in Table 1

Intermediate A22-Oxo-1-piperidin-4-yl-2,3-dihydro-1H-benzoimidazole-5-carboxylic acidallyl ester dihydrochloride

Step 1:1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid allyl ester

To a stirred solution of4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (20.0 g, 53.27 mmol, 1.0 equiv; example 1/step 4) intoluene (200 mL) and N-ethyldiisopropylamine (17.21 g, 133.17 mol, 2.5equiv) was added a solution of triphosgene (18.97 g, 63.92 mmol, 1.2equiv) in toluene (200 mL) and the reaction mixture stirred at 70° C.for 1.5 h. The solvent was evaporated, the residue diluted with waterand extracted with ethyl acetate. The combined organic fractions werewashed with water and a sat. solution of NaCl, dried over Na₂SO₄ andconcentrated by evaporation under reduced pressure. The crude materialwas further washed with a mixture of hexane/ethyl acetate (95:5) toyield 15.5 g (73%) of the title product as wvhite solid. ¹H NMR (400MHz, DMSO): δ 1.43 (s, 9H), 1.72 (d, J=10.8, 2H), 2.17-2.23 (m, 2H),2.88 (br s, 2H), 4.09 (d, J=8.6 Hz, 2H), 4.38 (t, J=12.2 Hz, 1H), 4.77(d, J=5.3 Hz, 2H), 5.26 (d, J=10.4 Hz, 1H), 5.40 (dd, J=17.2 Hz, J=1.4Hz, 1H), 5.99-6.09 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.3 Hz,1H), 7.69-7.71 (m, 1H), 11.17 (s, 1H). ¹³C-NMR (100 MHz, DMSO): δ 28.04,28.43, 50.32, 64.78, 78.79, 108.13, 109.18, 117.70, 121.69, 121.71,122.67, 128.20, 132.81, 133.39, 153.78, 153.82, 165.36. MS (ISP): 402.2[M+H]⁺.

Step 2:2-Oxo-1-piperidin-4-yl-2,3-dihydro-1H-benzoimidazole-5-carboxylic acidallyl ester dihydrochloride

A solution of1-(1-tert-butoxycarbonyl-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid allyl ester (1.40 g, 3.49 mmol) in dioxane (20 mL) and 4 M HCl indioxane (20 mL) was stirred at rt for 2 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 302.1 [M+H]⁺.

Intermediate A33-Oxo-1-piperidin-4-yl-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acidallyl ester dihydrochloride

Step 1:4-[4-Allyloxycarbonyl-2-(2-bromo-acetylamino)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (25.0 g, 66.58 mmol, 1.0 equiv; example 1/step 4) indichloromethane (250 mL) at 0° C. were slowly added triethylamine (16.84g, 166.46 mol, 2.5 equiv) and bromoacetyl chloride (20.96 g, 133.17 mol,2.0 equiv). After the addition was completed the cooling bath wasremoved and the reaction stirred for 2 h at rt. The reaction mixture wascooled again to 0° C., diluted with water and extracted with ethylacetate. The combined organic fractions were washed with water, driedover Na₂SO₄, concentrated by evaporation under reduced pressure andpurified with silica column chromatography eluting with hexane/ethylacetate (65:35) to obtain 23.1 g (70%) of the title compound. ¹H NMR(400 MHz, DMSO): δ 1.40 (s, 9H), 2.92 (br s, 2H), 3.62 (hr s, 1H), 4.03(d, J=7.1, 2H), 4.30 (s, 2H), 4.72 (d, J=5.1, 2H), 5.24 (dd, J=10.5 Hz,J=1.0, 1H), 5.35 (dd, J=16.6 H, J=0.7, 1H), 5.50 (d, J=7.7 Hz, 1H),5.98-6.05 (m, 1H), 6.82(d, J=8.8 Hz, 1H), 7.68 (dd, J=8.6 Hz, J=1.5 Hz,1H), 7.73 (d, J=1.3 Hz, 1H), 9.43 (s, 1H).

Step 2:1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid allyl ester

A mixture of4-[4-allyloxycarbonyl-2-(2-bromo-acetylamino)-phenylamino]-piperidine-1-carboxylicacid tert-butyl ester (23.0 g, 46.33 mmol, 1.0 equiv) andN-ethyldiisopropylamine (11.98 g, 92.67 mmol,2.0 equiv) in toluene (250mL) was heated to reflux. After 8 h, the reaction mixture was cooled,washed with water and concentrated by evaporation under reduced pressureand purified with silica column chromatography eluting withdichloromethane/acetone (95:5) to obtain 10.0 g (52%) of the titlecompound as yellow solid. ¹H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.65(br s, 4H), 2.89 (s, 2H), 3.74 (s, 2H), 3.90 (br s, 1H), 4.05 (br s,2H), 4.73 (d, J=5.1, 2H), 5.25 (d, J=10.4, 1H), 5.36 (dd, J=17.2 Hz,J=1.1 Hz, 1H), 5.98-6.05 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 7.44 (d, J=1.4Hz, 1H), 7.53 (dd, J=17.2 Hz, J=1.1 Hz, 1H), 10.58 (s, 1H). ¹³C-NMR (100MHz, DMSO): δ 26.87, 28.02, 45.15, 53.36, 64.35, 78.67, 110.81, 115.77,117.36, 118.04, 125.21, 126.61, 132.95, 132.99, 138.63, 153.70, 164.94,165.00. MS (ISP): 416.2 [M+H]⁺.

Step 3:3-Oxo-1-piperidin-4-yl-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acidallyl ester dihydrochloride

A solution of1-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid allyl ester (1.40 g, 3.37 mmol) in dioxane (20 mL) and 4 M HCl indioxane (20 mL) was stirred at rt for 2 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 316.1 [M+H]⁺.

Intermediate A4 1-Piperidin-4-yl-1H-benzotriazole-5-carboxylic acidallyl ester dihydrochloride

Step 1:1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-1H-benzotriazole-5-carboxylicacid allyl ester

To a solution of4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (50.0 g, 133.17 mmol, 1.0 equiv; example 1/step 4) inmethanol (400 mL) was added conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv)and the reaction mixture stirred at 0° C. for 2 h. Another portion ofconc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) was added and stirring wascontinued for an additional time period of 3 h. The reaction mixture wascooled to 0° C., diluted with water (25 mL), treated with a sat.solution of NaNO₂ (10.11 g, 146.48 mmol, 1.1 equiv) and stirred at rtfor 30 min. The reaction mixture was cooled to 0° C., basified byaddition of a sat. solution of NaHCO₃, concentrated by evaporation underreduced pressure and the aqueous phase extracted with ethyl acetate(3×150 mL). The organic solvents were to a large extent evaporated underreduced pressure and the aqueous layer was extracted with ethyl acetate(3×150 ml). The organic phase was washed with water, dried over Na₂SO₄and evaporated under reduced pressure. The residue which was a mixtureof the desired product and the de-boc analogue was treated withdi-tert-butyl dicarbonate (29.06 g, 133.17 mmol, 1.0 equiv) andN-ethyl-diisopropylamine (20.65 g, 159.80 mmol, 1.2 equiv) indichloromethane (200 mL). The solvent was evaporated under reducedpressure, water was added and the reaction mixture extracted with ethylacetate (3×100 mL). The organic layer was washed with water, dried overNa₂SO₄ and evaporated under reduced pressure. The crude material waspurified with silica column chromatography eluting with a gradient ofhexane/ethyl acetate (9:1→4:1) to obtain 37.1 g (72%) of the titlecompound. ¹H NMR (400 MHz, DMSO): δ 1.44 (s, 9H), 2.02-2.16 (m, 4H),3.05 (br s, 2H), 4.12-4.15 (m, 2H), 4.87 (d, J=5.2 Hz, 2H), 5.16-5.22(m, 1H), 5.30 (d, J=10.7, 1H), 5.45 (dd, J=17.2 Hz, J=1.0 Hz, 1H),6.06-6.13 (m, 1H), 8.08-8.15 (m, 2H), 8.68 (s, 1H). ¹³C-NMR (100 MHz,DMSO): δ 28.91, 32.21, 56.66, 66.25, 79.82, 112.04, 118.86, 122.44,126.56, 128.09, 133.42, 135.42, 145.66, 154.72, 165.86. MS (ISP): 387.3[M+H]⁺.

Step 2: 1-Piperidin-4-yl-1H-benzotriazole-5-carboxylic acid allyl esterdihydrochloride

A solution of1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-benzotriazole-5-carboxylicacid allyl ester (1.40 g, 3.62 mmol) in dioxane (20 mL) and 4 M HCl indioxane (20 mL) was stirred at rt for 2 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 287.3 [M+H]⁺.

Intermediate A5 1-Piperidin-4-yl-1,5-dihydro-imidazo[4,5-c]pyridin-4-onedihydrochloride

Step 1: 4-(3-Nitro-pyridin-4-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-chloro-3-nitro-pyridine (25.0 g, 157.69 mmol, 1.0equiv; commercially available) and triethylamine (19.15 g, 189.23 mol,1.2 equiv) in anhydrous DMF (100 mL) was added4-amino-piperidine-1-carboxylic acid tert-butyl ester (31.58 g, 157.69mmol, 1.0 equiv; commercially available), dissolved in anhydrous DMF (30mL), and the reaction mixture stirred at rt for 15 h. The reactionmixture was poured into ice-cold water (1 L) and stirred for 2 h,allowed to settle for another 2 h and then filtered. The orange solidwas washed with water and air-dried. The crude material was crystallizedfrom ethyl acetate to obtain 43.7 g (86%) of the title compound. ¹H NMR(400 MHz, DMSO): δ 1.41 (s, 9H), 1.48-1.56 (m, 2H), 1.88-1.90 (m, 2H),2.93 (br s, 2H), 3.90-3.93 (m, 3H), 7.14 (d, J=6.3 HZ, 1H), 8.03 (d,J=7.9 Hz, 1H), 8.27 (s, J=6.2 Hz, 1H), 9.03 (s, 1H).

Step 2: 4-(3-Amino-pyridin-4-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-(3-nitro-pyridin-4-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (25.0 g, 77.55 mmol, 1.0 equiv) in ethanol (375mL) was added palladium on activated charcoal 10% (2.5 g, 2.35 mmol,0.03 equiv) and the reaction put under hydrogen (50 Psi) in a Parrshaker for 16 h. The reaction mixture was filtered through Celite andthe filtrate evaporated under reduced pressure. The residue wastriturated with diethyl ether, the organic layer decanted and the solidmaterial dried under reduced pressure to yield 18.4 g (81%) of the titlecompound. ¹H NMR (400 MHz, DMSO): δ 1.25-1.27 (m, 2H), 1.40 (s, 9H),1.88-1.91 (m, 2H), 2.90 (br s, 2H), 3.49 (br s, 1H), 3.89 (br s, 2H),4.57 (s, 2H), 5.05 (br s, 1H), 6.42 (d, J=4.3 Hz, 1H), 7.56 (d, J=4.3Hz, 1H), 7.63 (s, 1H). MS (ISP): 293.4 [M+H]⁺.

Step 3: 4-Imidazo[4,5-c]pyridin-1-yl-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-(3-amino-pyridin-4-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (10.0 g, 34.20 mmol, 1.0 equiv) and triethylorthoformate (10.14 g, 68.40 mmol, 2.0 equiv) in anhydrous toluene (70mL) was added toluene-4-sulfonic acid (0.59 g, 3.42 mmol, 0.1 equiv) andthe reaction mixture heated to reflux for 16 h. The solvent was removedby evaporation under reduced pressure and the residue triturated withdiethyl ether. The preciptate was filtered off, washed with diethylether and dried under reduced pressure to yield 7.6 g (73%) of the titlecompound. ¹H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.92-2.04 (m, 4H),2.95 (br s, 2H), 4.13 (br s, 2H), 4.64 (t, J=3.8 Hz, 1H), 7.75 (d, J=5.5Hz, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.55 (s, 1H), 8.95 (s, 1H). MS (ISP):303.2 [M+H]¹.

Step 4: 4-(5-Oxy-imidazo[4,5-c]pyridin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 4-imidazo[4,5-c]pyridin-1-yl-piperidine-1-carboxylicacid tert-butyl ester (10.0 g, 33.07 mmol, 1.0 equiv) in anhydrousdichloromethane (100 mL) was added at 10° C. 3-chloro-perbenzoic acid(7.41 g, 33.07 mmol, 1.0 equiv; 77% purity) and the reaction mixturestirred at rt for 18 h. The solvent was removed under reduced pressureand the residue purified with neutral alumina column chromatographyeluting with a gradient of dichloromethane/methanol (95:5→70:30) toobtain 8.2 g (78%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.43(s, 9H), 1.86-1.95 (m, 2H), 2.02-2.05 (m, 2H), 2.92 (br s, 2H), 4.12 (brs, 2H), 4.63 (t, J=11.7 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H), 8.11 (d, J=5.9Hz, 1H), 8.62 (s, 1H), 8.69 (s, 1H). MS (ISP): 319.2 [M+H]⁺.

Step 5:1-(1-Acetyl-piperidin-4-yl)-1,5-dihydro-imidazo[4,5-c]pyridin-4-one

A solution of4-(5-oxy-imidazo[4,5-c]pyridin-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (10.0 g, 31.41 mmol, 1.0 equiv) in anhydrous aceticanhydride (100 mL) was heated to reflux for 18 h. The solvent wasremoved under reduced pressure and the residue purified with neutralalumina column chromatography eluting with dichloromethane/methanol(97:3) to obtain 4.7 g (57%) of the title compound. ¹H NMR (400 MHz,DMSO): δ 1.79-1.82 (m, 1H), 1.91-1.99 (m, 3H), 2.05 (s, 3H), 2.67 (t,J=11.8, 1H), 3.16-3.24 (m, 1H), 3.95-3.98 (m, 1H), 4.51-4.57 (m, 2H),6.68 (d, J=7.0 Hz, 1H), 7.16-7.19 (m, 1H), 8.12 (s, 1H), 11.17 (s, 1H).MS (ISP): 261.2 [M+H]⁺.

Step 6: 1-Piperidin-4-yl-1,5-dihydro-imidazo[4,5-c]pyridin-4-onedihydrochloride

To a solution of1-(1-acetyl-piperidin-4-yl)-1,5-dihydro-imidazo[4,5-c]pyridin-4-one(6.00 g, 23.05 mmol) in ethanol (48 mL) was added conc. HCl (24 mL) andthe reaction mixture heated to reflux for 16 h. The solvent was removedunder reduced pressure and the crude product used in the consecutivestep without further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 219.2 [M+H]⁺.

The aldehyde intermediates B1 to B20 were prepared following literatureprecedents or in analogy to literature precedents or as described below.

Synthesis of Aldehyde Intermediates B1 to B20 to be used in Table 1 andTable 2

Intermediate B1 3-Ethoxy-4-fluoro-benzaldehyde

The title compound was prepared according to the procedure described forthe synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate B2, videinfra) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overallyield after purification by flash column chromatography on silicaeluting with hexane/ethyl acetate (10:1). ¹H NMR (300 MHz, DMSO): δ 1.32(t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56(m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH₄]⁺.

Intermediate B2 4-Chloro-3-ethoxy-benzaldehyde [CAS RN 85259-46-71]

To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0equiv) in DMF (15 mL) was added K₂CO₃ (4.81 g, 34.8 mmol, 2.0 equiv) andethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reactionmixture was stirred for 6 h at rt, diluted with water (20 mL) andextracted, with ethyl acetate (3×50 mL). The organic phase was driedover Na₂SO₄ and concentrated to afford 3.6 g (91%) of4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was thendissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution ofdiisobutylaluminum hydride (95 ml, 95.0 mmol, 6.0 equiv; 1.0 M solutionin THF) was slowly added over a time period of 15 min, the cooling bathremoved after completion of addition and the reaction allowed to reach0° C. After stirring for 1 h, the reaction was cooled to −78° C. and theexcess of hydride quenched by cautious addition of a solution of 1 M HCl(10 mL). The mixture was warmed up to rt, the organic phase separatedand the aqueous layer extracted with ethyl acetate (3×100 mL). Thecombined organic phases were dried over Na₂SO₄ and concentrated byevaporation under reduced pressure providing 2.94 g (100%) of4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol,1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO₂(5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture wasstirred for 16 h, after which time the reaction was filtered throughHyflo Super Cel and concentrated. The residue was purified by flashcolumn chromatography on silica eluting with heptane/ethyl acetate (4:1)to yield 1.51 g (52%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55(d, J=9.0 Hz, 1H), 9.94 (s, 1H).

Intermediate B3 3-Ethoxy-4-(1-ethyl-propoxy)-benzaldehyde

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) byreaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMFusing K₂CO₃ as base. MS (ISP): 237.1 [M+H]⁺.

Intermediate B4 3-(2-Fluoro-ethoxy)-4-methoxy-benzaldehyde

To a solution of 3-hydroxy-4-methoxy-benzaldehyde (100 g, 66.0 mmol, 1.0equiv; commercially available) in anhydrous DMF (40 mL) was added K₂CO₃(13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K₂CO₃ wasremoved by filtration and the organic phase concentrated under reducedpressure. To the residue was added a sat. solution of NaCl (100 mL) andthe solution extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over MgSO₄ and the product crystallized from amixture of isopropanol/diethyl ether to yield 12.69 g (97%) of the titlecompound. ¹H NMR (300 MHz, DMSO): δ 3.89 (s, 3H), 4.24-4.27 (m, 1H),4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84(s, 1H). MS (ISP): 198.6 [M+H]⁺.

Intermediate B5 3-Isobutoxy-4-methoxy-benzaldehyde [CAS RN 57724-26-21]

The title compound was prepared by reaction of isovanillin with1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion AG).

Intermediate B6 8-Ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde [CAS RN210404-30-9]

The title compound was prepared according to WO 01/083 476 A1(Hoffmann-La Roche AG).

Intermediate B7 3,5-Diethoxy-benzaldehyde [CAS RN 120355-79-5]

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) byreaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF usingK₂CO₃ as base.

Intermediate B8 3,5-Diisopropoxy-benzaldehyde [CAS RN 94169-64-9]

To a solution of 3,5-dihydroxy-benzaldehyde (5.0 g, 36.20 mmol, 1.0equiv) in anhydrous DMF (30 mL) was added K₂CO₃ (15.0 g, 108.60 mmol,3.0 equiv) and 2-bromo-propane (13.36 g, 10.20 mL, 108.60 mmol, 3.0equiv) and the mixture stirred at 100° C. for 18 h. The K₂CO₃ wasremoved by filtration and the organic phase concentrated under reducedpressure. To the residue was added a sat. solution of NaCl (100 mL) andthe solution extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over MgSO₄ and the product purified by silicacolumn chromatography using a MPLC system (CombiFlash Companion, IscoInc.) cluting with a gradient of heptane/ethyl acetate affording 6.64 g(83%) of the title compound and 0.59 g (9%) of3-hydroxy-5-isopropoxy-benzaldehyde. ¹H NMR (300 MHz, CDCl₃): δ 1.35 (d,J=6.1 Hz, 12H), 4.59 (hept, J=6.1 Hz, 2H), 6.66-6.68 (m, 1H), 6.96-6.97(m, 2H), 9.88 (s, 1H). MS (ISP): 223.1 [M+H]⁺.

Intermediate B9 2,6-Diethoxy-4-formyl-benzoic acid ethyl ester [CAS RN55687-55-3]

The title compound was prepared as described in DE 243 59 34(Hoffmann-La Roche AG).

Intermediate B10 3,5-Diethoxy-4-fluoro-benzaldehyde

Step 1: tert-Butyl-(4-fluoro-benzyloxy)-dimethyl-silane

To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole(7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane(15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed thecooling bath was removed and the reaction stirred for 18 h at rt. Thereaction mixture was poured on ice, extracted with ethyl acetate (2×100mL) and the combined organic phases washed with a sat. solution ofNa₂CO₃ (2×100 mL) and a sat. solution of NaCl (2×100 mL). The organicphase was dried over Na₂SO₄, concentrated by evaporation under reducedpressure yielding a brown oil that was purified by high vacuumdestillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (s, 6H), 0.84 (s, 9H),4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1[M-tert-Bu]⁺.

Step 2: 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of tert-butyl-(4-fluoro-benzyloxy)-dimethyl-silane (5.00g, 20.8 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added at −78° C.under Ar a solution of sec-BuLi (17.6 mL, 22.8 mmol, 1.1 equiv; 1.3 Msolution in hexane) within 30 min. Then a solution of trimethyl borate(2.37 mL, 2.20 g, 20.8 mmol, 1.0 equiv) in anhydrous THF (7.5 mL) wasadded slowly within 30 min and the cooling bath removed. A solution ofconc. acetic acid (2.78 mL, 1.87 g, 31.2 mmol, 1.5 equiv) was slowlyadded followed by a solution of 35% hydrogen peroxide in water (2.0 mL,2.23 g, 22.9 mmol, 1.1 equiv) and the reaction allowed to proceed at 0°C. for another 30 min. After stirring at rt for additional 4 h, themixture was extracted with diethyl ether (2×100 mL) and the combinedorganic phases washed with a solution of 10% NaOH (2×100 mL) and a sat.solution of NaCl (2×100 mL). The organic phase was dried over Na₂SO₄,concentrated by evaporation under reduced pressure and the crudematerial purified with column chromatography on silica eluting withhexane/ethyl acetate (19:1) providing 4.80 g (90%) of the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (s, 6H), 0.84 (s, 9H), 4.56(s, 2H), 4.97 (br s, 1H), 6.68-6.72 (m, 1H), 6.87-6.94 (m, 2H). MS (EI):256.2 [M]⁺.

Step 3:2-(tert-Butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene

To a solution of5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was addedimidazole (1.34 g, 19.7 mmol, 1.1 equiv) andtert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). Afterthe addition was completed the cooling bath was removed and the reactionstirred for 18 h at rt. The reaction mixture was poured on ice,extracted with ethyl acetate (2×100 mL) and the combined organic phaseswashed with a sat. solution of Na₂CO₃ (2×100 mL) and a sat. solution ofNaCl (2×100 mL). The organic phase was dried over Na₂SO₄ andconcentrated by evaporation under reduced pressure yielding 4.50 g (68%)of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (s, 6H), 0.10 (s,6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H),6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (EI): 370.2 [M]⁺.

Step 4:3-(tert-Butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene(23.70 g, 63.9 mmol) 1.0 equiv) in anhydrous THF (130 mL) was added at−78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 equiv;1.3 M solution in hexane) within 30 min. Then a solution of trimethylborate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (30 mL)was added slowly within 30 min and the cooling bath removed. A solutionof conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 equiv) was slowlyadded followed by addition of a solution of 35% hydrogen peroxide inwater (6.2 mL, 6.83 g, 70.3 mmol, 1.1 equiv) and the reaction allowed toproceed at 0° C. for another 30 min. After stirring at rt for additional4 h, the mixture was extracted with diethyl ether (2×100 ml.) and thecombined organic phases washed with a solution of 10% NaOH (2×100 mL)and a sat. solution of NaCl (2×100 mL). The organic phase was dried overNa₂SO₄, concentrated by evaporation under reduced pressure, and thecrude material was purified with column chromatography on silica elutingwith hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85(s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz,1H), 6.47 (d, J=5.6 Hz, 1H). MS (EI): 329.2 [M-tert-Bu]⁺.

Step 5: tert-Butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane

To a solution of3-(tert-butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol(5.80 g, 15.0 mmol, 1.0 equiv) in DMF (60 mL) was added K₂CO₃ (4.56 g,33.0 mmol, 2.2 equiv) and ethyl bromide (2.46 mL, 3.60 g, 33.0 mmol, 2.2equiv) and the reaction mixture stirred under Ar at 60° C. for 5 h. TheK₂CO₃ was removed by filtration, the crude reaction mixture concentratedby evaporation under reduced pressure, the residue extracted with ethylacetate (3×100 mL), the combined organic phases washed with water (2×100ml) and dried over Na₂SO₄. The solvent was removed by evaporation underreduced pressure and the crude material purified with columnchromatography on silica eluting with hexane/ethyl acetate (99:1)providing 3.10 g (63%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.85 (s, 9H), 1.33 (t, J=7.0 Hz, 6H), 4.00 (q, J=7.0 Hz,4H), 4.55 (s, 2H), 6.47 (d, J=6.8 Hz, 2H). MS (ISP): 329.3 [M+H]⁺.

Step 6: (3,5-Diethoxy-4-fluoro-phenyl)-methanol

To a solution oftert-butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane (1.20 g,3.65 mmol, 1.0 equiv) in methanol (8 mL) was added Dowex 50W-X8 (0.33 g,cation exchange resin) and the reaction mixture stirred under Ar at rtfor 22 h. The resin was removed by filtration and the reaction mixtureconcentrated by evaporation under reduced pressure yielding the titlecompound in quantitative yield (0.78 g). ¹H NMR (400 MHz, CDCl₃): δ 1.34(t, J=7.0 Hz, 6H), 1.57 (t, J=5.4 Hz, 1H), 4.01 (q, J=7.0 Hz, 4H), 4.51(d, J=5.4 Hz, 2H), 6.51 (d, J=6.8 Hz, 2H). MS (EI): 214.2 [M]⁺.

Step 7: 3,5-Diethoxy-4-fluoro-benzaldehyde

To a solution of (3,5-diethoxy-4-fluoro-phenyl)-methanol (2.30 g, 10.7mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added activated MnO₂(2.89 g, 33.3 mmol, 3.1 equiv). The reaction mixture was stirred for 21h at 50° C. and then filtered through Hyflo Super Cel providing afterevaporation of the solvent under reduced pressure 1.90 g (83%) of thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 1.38 (t, J=7.0 Hz, 6H), 4.09(q, J=7.0 Hz, 4H), 7.04 (d, J=7.2 Hz, 2H), 9.75 (s, 1H). MS (EI): 212.1[M]⁺.

Intermediate B1 4-Chloro-3,5-diethoxy-benzaldehyde

Step 1: 4-Chloro-3,5-diethoxy-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g,20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. WickHelv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv).After 10 min, copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) wasadded, the reaction mixture stirred for an additional 5 h at 0° C. andthen the ice bath removed. After stirring for 18 h, the crude reactionmixture was adjusted to pH=8 by addition of a solution of 1 M NaOH andthe aqueous layer extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over MgSO₄, concentrated by evaporation underreduced pressure and the crude material purified by silica columnchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%)of the title compound. ¹H NMR (300 MHz, CDCl₃): δ 1.32 (t, J=7.0 Hz,4H), 1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz,2H), 7.18 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 13.33, 13.66, 60.29,64.16, 105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]⁺.

Step 2: (4-Chloro-3,5-diethoxy-phenyl)-methanol

To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g,18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly overa time period of 15 min under slight cooling to −30° C. a solution ofdiisobutylaluminum hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1.0 Msolution in THF). After 30 min, the excess of hydride was quenched bycautious addition of methanol (10 mL) and water (2 mL). The mixture wasstirred for 30 min, a solution of 1 M HCl was added and the aqueouslayer extracted with ethyl acetate (3×100 mL). The combined organicphases were dried over MgSO₄ and concentrated by evaporation underreduced pressure providing 4.0 g (95%) of the title compound. ¹H NMR(300 MHz, CDCl₃): δ 1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q,J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4[M+H]⁻.

Step 3:

To a solution of (4-chloro-3,5-diethoxy-phenyl)-methanol (4.0 g, 17.34mmol, 1.0 equiv) in THF (40 mL) was added activated MnO₂ (15.08 g, 173.4mmol, 10.0 equiv) and the reaction mixture stirred for 18 h at rt.Filtration through Hyflo Super Cel and purification of the crudematerial by silica column chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of heptane/ethyl acetateprovided 3.7 g (92%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.50 (t, J=7.0 Hz, 6H), 4.19 (q, J=7.0 Hz, 4H), 7.07 (s, 2H), 9.89 (s,1H). ¹³C NMR (75 MHz, CDCl₃): δ 14.61, 65.22, 106.26, 118.64, 135.08,156.22, 191.01. MS (EI): 229.4 [M]⁺.

Intermediate B12 4-Bromo-3,5-diethoxy-benzaldehyde [CAS RN 363166-11-4]

The title compound was prepared from 4-bromo-3,5-dihydroxy-benzoic acidas described in S. P. Dudek, H. D. Sikes and C. E. D. Chidsey J. Am.Chem. Soc. 2001, 123, 8033-8038.

Intermediate B13 4-Amino-3,5-diethoxy-benzaldehyde

Step 1: (4-Amino-3,5-diethoxy-phenyl)-methanol

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (2.8 g,11.05 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick,Helv. Chim. Acta 1977, 60, 3025-3034) in dichloromethane (50 mL) at 0°C. under Ar was slowly added diisobutylaluminum hydride (27.6 mL, 27.64mmol, 2.5 equiv; 1.0 M solution in dichloromethane) over a time periodof 15 min and the cooling bath removed on completion of addition. Afterstirring for 18 h, the excess of hydride was quenched by cautiousaddition of a sat. solution of potassium sodium tartrate (10 mL). Thesolidified mixture was extracted with dichloromethane (5×200 mL) and THF(2×150 mL), the combined organic phases washed with water (3×100 mL),dried over MgSO₄, concentrated by evaporation under reduced pressure andthe crude material purified by column chromatography on silica elutingwith a gradient of heptane/ethyl acetate (4:1→1:1) providing 1.10 g(47%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ 1.42 (t, J=7.0Hz, 3H), 3.82 (br s, 2H), 4.05 (q, J=7.0 Hz, 2H), 4.54 (s, 2H), 6.50 (s,2H). ¹³C NMR (75 MHz, CDCl₃): δ 15.03, 66.00 104.51, 125.44, 129.89,146.71. MS (ISP): 211.9 [M+H]⁺.

Step 2: 4-Amino-3,5-diethoxy-benzaldehyde

To a solution of (4-amino-3,5-diethoxy-phenyl)-methanol (0.79 g, 3.74mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO₂ (1.63 g, 18.70mmol, 5.0 equiv). The reaction mixture was stirred for 24 h at rt,filtered through Hyflo Super Cel, the filtrate was extracted with ethylacetate (3×50 mL), and the combined organic phase was washed with water,dried over MgSO₄ and evaporated to dryness providing thereby 0.69 g(88%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.46 (t, J=7.0Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.50 (br s, 2H), 7.04 (s, 2H), 9.70 (s,1H). MS (ISP): 210.0 [M+H]⁺.

Intermediate B14 3,5-Diethoxy-4-pyrrol-1-yl-benzaldehyde

Step 1: 3,5-Diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g,11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick,Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc.acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g,14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Starkapparatus was attached and the reaction mixture heated for an additionaltime period of 5 h. Filtration of the crude reaction mixture andcrystallization at 0° C. from heptane provided 2.94 g (82%) of the titlecompound. ¹H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t,J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08(m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). ¹³C NMR (75 MHz, DMSO): δ14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29,153.75, 165.06. MS (ISP): 303.4 [M+H]⁺.

Step 2: 3,5-Diethoxy-4-pyrrol-1-yl-benzaldehyde

To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester(1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over atime period of 15 min under slight cooling to 20° C. a solution ofdiisobutylaluminum hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solutionin toluene). After 1 h, the excess of hydride was quenched by cautiousaddition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixturewas stirred for 30 min and the organic phase filtered over Hyflo SuperCel. The aqueous layer was extracted with toluene (2×50 mL), thecombined organic phases washed with a sat. solution of NaCl (2×50 mL)and concentrated by evaporation under reduced pressure to afford 1.30 g(100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crudealcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL),and activated MnO₂ (7.79 g, 89.5 mmol, 18.0 equiv) was added. Thereaction mixture was heated to reflux for 7 h, after which time thereaction mixture was filtered through Hyflo Super Cel and concentratedyielding 1.15 g (89% yield) of the title compound. ¹H NMR (300 MHz,DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m,2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1[M+H]⁺.

Intermediate B15 2,6-Diethoxy-4′-fluoro-biphenyl-4-carbaldehyde

3,5-Diethoxy-4-iodo-benzaldehyde (14.05 g, 43.89 mmol, 1.0 equiv;prepared as described in WO 01/326 33 A1 (F. Hoffmann-La Roche AG); [CASRN 338454-05-0]) was dissolved under Ar in toluene (180 mL) and water(20 mL) and treated successively with 4-fluorophenyl boronic acid (12.28g, 87.78 mmol, 2.0 equiv), K₃PO₄ (50.12 g, 236.12 mmol, 5.38 equiv),tricyclohexylphosphine (2.80 g, 9.66 mmol, 0.22 equiv) and palladium(II)acetate (1.08 g, 4.83 mmol, 0.11 equiv). The reaction mixture was heatedto 100° C. for 18 h under scrupulous exclusion of oxygen, when GCindicated the absence of starting iodo-compound. The reaction mixturewas poured on crashed ice/NH₄Cl, extracted with ethyl acetate (2×200 mL)and the combined organic phases washed with a sat. solution of NaCl(2×100 mL) and water (2×100 mL). The organic phase was dried overNa₂SO₄, concentrated by evaporation under reduced pressure and the crudematerial purified by silica column chromatography eluting with a mixtureof hexane/ethyl acetate (9:1). Recrystallization from hexane/ethylacetate provided 10.44 g (83%) of the title compound as white crystals.MS (EI): 288.2 [M]⁺.

Intermediate B16 4-Methoxy-3-propoxy-benzaldehyde [CAS RN 5922-56-5]

The title compound was prepared by reaction of isovanillin with propyliodide in DMF using K₂CO₃ as base in analogy to the preparation of3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra).

Intermediate B17 3-Butoxy-4-methoxy-benzaldehyde

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) byreaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMFusing K₂CO₃ as base. MS (ISP): 209.1 [M+H]⁺.

Intermediate B18 3-Allyloxy-4-methoxy-benzaldehyde [CAS RN 225939-36-6]

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) byreaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMFusing K₂CO₃ as base (see also A. W. White, R. Almassy, A. H. Calvert, N.J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S.Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).

Intermediate B19 3-Ethoxy-4-methyl-benzaldehyde [CAS RN 157143-20-9]

The title compound was prepared by reaction of commercially available3-hydroxy-4-methyl-benzaldehyde with ethyl iodide in DMF using K₂CO₃ asbase in analogy to the procedure described in M. J. Ashton, D. C. Cook,G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J.Ratcliffe, J. E. Souness, S. Thurairatnam and N. Vicker J. Med. Chem.1994, 37, 1696-1703.

Intermediate B20 2-Ethoxy-4′-fluoro-biphenyl-4-carbaldehyde

Step 1: 2-Ethoxy-4′-fluoro-biphenyl-4-carboxylic acid ethyl ester

To a solution of 3-ethoxy-4-iodo-benzoic acid ethyl ester (0.76 g, 2.37mmol, 1.0 equiv; [CAS RN 741699-04-7]) in anhydrous DMF (12 mL) under Arwas added 4-fluorophenyl boronic acid (0.40 g, 2.86 mmol, 1.20 equiv),K₃PO₄ (0.86 g, 4.04 mmol, 1.70 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol, 0.03 equiv) and the reaction mixtureheated to 80° C. After 16 h, the reaction mixture was poured on crashedice/NH₄Cl, extracted twice with ethyl acetate, the combined organicphases washed with water and a sat. solution of NaCl, dried over MgSO₄and concentrated by evaporation under reduced pressure. The crudematerial was purified with silica column chromatography eluting withhexane/ethyl acetate (95:5) to yield 0.51 g (75%) of the title compoundas a colorless oil. MS (ISP): 289.3 [M+H]⁺.

Step 2: (2-Ethoxy-4′-fluoro-biphenyl-4-yl)-methanol

To a solution of 2-ethoxy-4′-fluoro-biphenyl-4-carboxylic acid ethylester (0.50 g, 1.73 mmol, 1.0 equiv) in anhydrous THF (10 mL) was addeddropwise at −10° C. diisobutylaluminum hydride (5.2 mL, 5.20 mmol, 3.0equiv; 1 M solution in hexane) and the ccolong bath removed. Afterstirring for an additional time period of 60 min at rt, the reactionmixture was carefully poured on crashed ice/diluted HCl, extracted twicewith ethyl acetate, the combined organic phases washed with water and asat. solution of NaCl, dried over MgSO₄ and concentrated by evaporationunder reduced pressure. The title compound was isolated in quantitativeyield (0.43 g) as a colorless viscous oil, sufficiently pure for thenext step. MS (ISP): 229.3 [M+H—H₂O]¹.

Step 3: 2-Ethoxy-4′-fluoro-biphenyl-4-carbaldehyde

To a solution of (2-ethoxy-4′-fluoro-biphenyl-4-yl)-methanol (0.43 g,1.75 mmol, 1.0 equiv) in dichloromethane (20 mL) was added activatedMnO₂ (3.04 g, 34.92 mmol, 20.0 equiv) and the reaction mixture stirredvigorously for 3 h at ambient temperature. The reaction mixture wasfiltered over a pad of Celite, rinsed generously with dichloromethaneand evaporated to dryness under reduced pressure. The crude material waspurified with silica column chromatography eluting with hexane/ethylacetate (4:1) to yield 0.33 g (77%) of the title compound as whitecrystals. MS (EI): 244.1 [M]⁺.

Examples 2 to 102

According to the procedure described for the synthesis of example 1/step7 further benzoimidazole, tetrahydro-quinoxaline, benzotriazole anddihydro-imidazo[4,5-c]pyridinone derivatives have been synthesized from2-methyl-1-piperidin-4-yl-1H-benzoimidazole-5-carboxylic acid allylester dihydrochloride (intermediate A1),2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-benzoimidazole-5-carboxylic acidallyl ester dihydrochloride (intermediate A2),3-oxo-1-piperidin-4-yl-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acidallyl ester dihydrochloride (intermediate A3),1-piperidin-4-yl-1H-benzotriazole-5-carboxylic acid allyl esterdihydrochloride (intermediate A4) and1-piperidin-4-yl-1,5-dihydro-imidazo[4,5-c]pyridin -4-onedihydrochloride (intermediate A5) and the respective benzaldehydeintermediate as indicated in Table 1. The results are compiled in Table1 and comprise example 2 to example 102.

TABLE 1 ISP No MW Compound Name Starting Materials [M + H]⁺ 2 427.931-[1-(4-chloro-3- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ ethoxy-benzyl)-benzoimidazole-5-carboxylic 428.3 piperidin-4-yl]-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-4-chloro-3-ethoxy-benzaldehyde carboxylic acid (intermediate B2) 3449.55 1-[1-(4-allyloxy-3- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ethoxy-benzyl)- benzoimidazole-5-carboxylic 450.4 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 4-allyloxy-3-ethoxy- carboxylic acid benzaldehyde(commercially available) 4 451.57 1-[1-(3-ethoxy-4-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ isopropoxy-benzyl)-benzoimidazole-5-carboxylic 452.3 piperidin-4-yl]-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-3-ethoxy-4-isopropoxy- carboxylic acid benzaldehyde (commerciallyavailable) 5 465.59 1-[1-(3-ethoxy-4- 2-methyl-1-piperidin-4-yl-1H- [M +H]⁺ isobutoxy-benzyl)- benzoimidazole-5-carboxylic 466.4piperidin-4-yl]-2- acid allyl ester dihydrochloride methyl-1H-(intermediate A1) and benzoimidazole-5- 3-ethoxy-4-isobutoxy- carboxylicacid benzaldehyde (commercially available) 6 479.62 1-{1-[3-ethoxy-4-(1-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ ethyl-propoxy)-benzyl]-benzoimidazole-5-carboxylic 480.4 piperidin-4-yl}-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-3-ethoxy-4-(1-ethyl-propoxy)- carboxylic acid benzaldehyde (intermediateB3) 7 477.60 1-[1-(4-cyclopentyloxy- 2-methyl-1-piperidin-4-yl-1H- [M +H]⁺ 3-ethoxy-benzyl)- benzoimidazole-5-carboxylic 478.4piperidin-4-yl]-2- acid allyl ester dihydrochloride methyl-1H-(intermediate A1) and benzoimidazole-5- 4-cyclopentyloxy-3-ethoxy-carboxylic acid benzaldehyde (commercially available) 8 499.611-[1-(4-benzyloxy-3- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ethoxy-benzyl)- benzoimidazole-5-carboxylic 500.4 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 4-benzyloxy-3-ethoxy- carboxylic acid benzaldehyde(commercially available) 9 459.49 1-[1-(4- 2-methyl-1-piperidin-4-yl-1H-[M + H]⁺ difluoromethoxy-3- benzoimidazole-5-carboxylic 460.3ethoxy-benzyl)- acid allyl ester dihydrochloride piperidin-4-yl]-2-(intermediate A1) and methyl-1H- 4-difluoromethoxy-3-ethoxy-benzoimidazole-5- benzaldehyde (commercially carboxylic acid available)10 437.54 1-[1-(3-isopropoxy-4- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺methoxy-benzyl)- benzoimidazole-5-carboxylic 438.4 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 3-isopropoxy-4-methoxy- carboxylic acid benzaldehyde(commercially available) 11 441.50 1-{1-[3-(2-fluoro-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ ethoxy)-4-methoxy-benzoimidazole-5-carboxylic 442.3 benzyl]-piperidin-4-yl}- acid allylester dihydrochloride 2-methyl-1H- (intermediate A1) andbenzoimidazole-5- 3-(2-fluoro-ethoxy)-4-methoxy- carboxylic acidbenzaldehyde (intermediate B4) 12 451.57 1-[1-(3-isobutoxy-4-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ methoxy-benzyl)-benzoimidazole-5-carboxylic 452.3 piperidin-4-yl]-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-3-isobutoxy-4-methoxy- carboxylic acid benzaldehyde (intermediate B5) 13463.58 1-[1-(3-cyclopentyloxy- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺4-methoxy-benzyl)- benzoimidazole-5-carboxylic 464.4 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 3-cyclopentyloxy-4-methoxy- carboxylic acidbenzaldehyde (commercially available) 14 475.59 1-[1-(8-ethoxy-2,2-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ dimethyl-2H-chromen-benzoimidazole-5-carboxylic 476.4 6-ylmethyl)-piperidin- acid allylester dihydrochloride 4-yl]-2-methyl-1H- (intermediate A1) andbenzoimidazole-5- 8-ethoxy-2,2-dimethyl-2H- carboxylic acidchromene-6-carbaldehyde (intermediate B6) 15 437.54 1-[1-(3,5-diethoxy-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ benzyl)-piperidin-4-yl]-benzoimidazole-5-carboxylic 438.4 2-methyl-1H- acid allyl esterdihydrochloride benzoimidazole-5- (intermediate A1) and carboxylic acid3,5-diethoxy-benzaldehyde (intermediate B7) 16 465.591-[1-(3,5-diisopropoxy- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺benzyl)-piperidin-4-yl]- benzoimidazole-5-carboxylic 466.4 2-methyl-1H-acid allyl ester dihydrochloride benzoimidazole-5- (intermediate A1) andcarboxylic acid 3,5-diisopropoxy-benzaldehyde (intermediate B8) 17509.60 1-[1-(3,5-diethoxy-4- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ethoxycarbonyl- benzoimidazole-5-carboxylic 510.4benzyl)-piperidin-4-yl]- acid allyl ester dihydrochloride 2-methyl-1H-(intermediate A1) and benzoimidazole-5- 2,6-diethoxy-4-formyl-benzoiccarboxylic acid acid ethyl ester (intermediate B9) 18 455.531-[1-(3,5-diethoxy-4- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺fluoro-benzyl)- benzoimidazole-5-carboxylic 456.4 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 3,5-diethoxy-4-fluoro- carboxylic acid benzaldehyde(intermediate B10) 19 471.98 1-[1-(4-chloro-3,5-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ diethoxy-benzyl)-benzoimidazole-5-carboxylic 472.3 piperidin-4-yl]-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-4-chloro-3,5-diethoxy- carboxylic acid benzaldehyde (intermediate B11)20 516.44 1-[1-(4-bromo-3,5- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺diethoxy-benzyl)- benzoimidazole-5-carboxylic 518.3 piperidin-4-yl]-2-acid allyl ester dihydrochloride methyl-1H- (intermediate A1) andbenzoimidazole-5- 4-bromo-3,5-diethoxy- carboxylic acid benzaldehyde(intermediate B12) 21 452.55 1-[1-(4-amino-3,5-2-methyl-1-piperidin-4-yl-1H- [M + H]⁺ diethoxy-benzyl)-benzoimidazole-5-carboxylic 453.4 piperidin-4-yl]-2- acid allyl esterdihydrochloride methyl-1H- (intermediate A1) and benzoimidazole-5-4-amino-3,5-diethoxy- carboxylic acid benzaldehyde (intermediate B13) 22502.61 1-[1-(3,5-diethoxy-4- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺pyrrol-1-yl-benzyl)- benzoimidazole-5-carboxylic 503.4piperidin-4-yl]-2- acid allyl ester dihydrochloride methyl-1H-(intermediate A1) and benzoimidazole-5- 3,5-diethoxy-4-pyrrol-1-yl-carboxylic acid benzaldehyde (intermediate B14) 23 531.631-[1-(2,6-diethoxy-4′- 2-methyl-1-piperidin-4-yl-1H- [M + H]⁺fluoro-biphenyl-4- benzoimidazole-5-carboxylic 532.4ylmethyl)-piperidin-4- acid allyl ester dihydrochloride yl]-2-methyl-1H-(intermediate A1) and benzoimidazole-5- 2,6-diethoxy-4′-fluoro-biphenyl-carboxylic acid 4-carbaldehyde (intermediate B15) 24 413.451-[1-(3-ethoxy-4- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ fluoro-benzyl)-dihydro-1H-benzoimidazole-5- 414.3 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-ethoxy-4-fluoro-benzaldehyde(intermediate B1) 25 429.90 1-[1-(4-chloro-3-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ ethoxy-benzyl)-dihydro-1H-benzoimidazole-5- 430.3 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 4-chloro-3-ethoxy-benzaldehyde(intermediate B2) 26 411.46 1-[1-(3-ethoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ hydroxy-benzyl)-dihydro-1H-benzoimidazole-5- 412.2 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-ethoxy-4-hydroxy-benzaldehyde (commercially available) 27 425.48 1-[1-(3-ethoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ methoxy-benzyl)-dihydro-1H-benzoimidazole-5- 426.3 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-ethoxy-4-methoxy-benzaldehyde (commercially available) 28 439.51 1-[1-(3,4-diethoxy-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ benzyl)-piperidin-4-yl]-dihydro-1H-benzoimidazole-5- 440.3 2-oxo-2,3-dihydro-1H- carboxylic acidallyl ester benzoimidazole-5- dihydrochloride (intermediate carboxylicacid A2) and 3,4-diethoxy-benzaldehyde (commercially available) 29451.52 1-[1-(4-allyloxy-3- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ethoxy-benzyl)- dihydro-1H-benzoimidazole-5- 452.3piperidin-4-yl]-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid4-allyloxy-3-ethoxy- benzaldehyde (commercially available) 30 453.541-[1-(3-ethoxy-4- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺isopropoxy-benzyl)- dihydro-1H-benzoimidazole-5- 454.3piperidin-4-yl]-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 31 467.571-[1-(3-ethoxy-4- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺isobutoxy-benzyl)- dihydro-1H-benzoimidazole-5- 468.4piperidin-4-yl]-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid3-ethoxy-4-isobutoxy- benzaldehyde (commercially available) 32 481.591-{1-[3-ethoxy-4-(1- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ethyl-propoxy)-benzyl]- dihydro-1H-benzoimidazole-5- 482.4piperidin-4-yl}-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid3-ethoxy-4-(1-ethyl-propoxy)- benzaldehyde (intermediate B3) 33 479.581-[1-(4-cyclopentyloxy- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺3-ethoxy-benzyl)- dihydro-1H-benzoimidazole-5- 480.4piperidin-4-yl]-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid4-cyclopentyloxy-3-ethoxy- benzaldehyde (commercially available) 34501.58 1-[1-(4-benzyloxy-3- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ethoxy-benzyl)- dihydro-1H-benzoimidazole-5- 502.4piperidin-4-yl]-2-oxo- carboxylic acid allyl ester 2,3-dihydro-1H-dihydrochloride (intermediate benzoimidazole-5- A2) and carboxylic acid4-benzyloxy-3-ethoxy- benzaldehyde (commercially available) 35 461.461-[1-(4- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ difluorormethoxy-3-dihydro-1H-benzoimidazole-5- 462.3 ethoxy-benzyl)- carboxylic acid allylester piperidin-4-yl]-2-oxo- dihydrochloride (intermediate2,3-dihydro-1H- A2) and benzoimidazole-5- 4-difluoromethoxy-3-ethoxy-carboxylic acid benzaldehyde (commercially available) 36 439.511-[1-(4-methoxy-3- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ propoxy-benzyl)-dihydro-1H-benzoimidazole-5- 440.4 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 4-methoxy-3-propoxy-benzaldehyde (intermediate B16) 37 443.47 1-{1-[3-(2-fluoro-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ ethoxy)-4-methoxy-dihydro-1H-benzoimidazole-5- 444.3 benzyl]-piperidin-4-yl}- carboxylicacid allyl ester 2-oxo-2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-(2-fluoro-ethoxy)-4-methoxy-benzaldehyde (intermediate B4) 38 453.54 1-[1-(3-butoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ methoxy-benzyl)-dihydro-1H-benzoimidazole-5- 454.4 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-butoxy-4-methoxy-benzaldehyde (intermediate B17) 39 453.54 1-[1-(3-isobutoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ methoxy-benzyl)-dihydro-1H-benzoimidazole-5- 454.3 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-isobutoxy-4-methoxy-benzaldehyde (intermediate B5) 40 465.55 1-[1-(3-cyclopentyloxy-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ 4-methoxy-benzyl)-dihydro-1H-benzoimidazole-5- 466.4 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3-cyclopentyloxy-4-methoxy-benzaldehyde (commercially available) 41 477.56 1-[1-(8-ethoxy-2,2-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ dimethyl-2H-chromen-dihydro-1H-benzoimidazole-5- 478.4 6-ylmethyl)-piperidin- carboxylicacid allyl ester 4-yl]-2-oxo-2,3- dihydrochloride (intermediatedihydro-1H- A2) and benzoimidazole-5- 8-ethoxy-2,2-dimethyl-2H-carboxylic acid chromene-6-carbaldehyde (intermediate B6) 42 439.511-[1-(3,5-diethoxy- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺benzyl)-piperidin-4-yl]- dihydro-1H-benzoimidazole-5- 440.32-oxo-2,3-dihydro-1H- carboxylic acid allyl ester benzoimidazole-5-dihydrochloride (intermediate carboxylic acid A2) and3,5-diethoxy-benzaldehyde (intermediate B7) 43 467.571-[1-(3,5-diisopropoxy- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺benzyl)-piperidin-4-yl]- dihydro-1H-benzoimidazole-5- 468.42-oxo-2,3-dihydro-1H- carboxylic acid allyl ester benzoimidazole-5-dihydrochloride (intermediate carboxylic acid A2) and3,5-diisopropoxy-benzaldehyde (intermediate B8) 44 511.571-[1-(3,5-diethoxy-4- 2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ethoxycarbonyl- dihydro-1H-benzoimidazole-5- 512.4benzyl)-piperidin-4-yl]- carboxylic acid allyl ester2-oxo-2,3-dihydro-1H- dihydrochloride (intermediate benzoimidazole-5-A2) and carboxylic acid 2,6-diethoxy-4-formyl-benzoic acid ethylester_(intermediate B9) 45 457.50 1-[1-(3,5-diethoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ fluoro-benzyl)-dihydro-1H-benzoimidazole-5- 458.2 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3,5-diethoxy-4-fluoro-benzaldehyde (intermediate B10) 46 473.96 1-[1-(4-chloro-3,5-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ diethoxy-benzyl)-dihydro-1H-benzoimidazole-5- 474.2 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 4-chloro-3,5-diethoxy-benzaldehyde (intermediate B11) 47 518.41 1-[1-(4-bromo-3,5-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ diethoxy-benzyl)-dihydro-1H-benzoimidazole-5- 518.3 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 4-bromo-3,5-diethoxy-benzaldehyde (intermediate B12) 48 454.53 1-[1-(4-amino-3,5-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ diethoxy-benzyl)-dihydro-1H-benzoimidazole-5- 455.4 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 4-amino-3,5-diethoxy-benzaldehyde (intermediate B13) 49 504.59 1-[1-(3,5-diethoxy-4-2-oxo-1-piperidin-4-yl-2,3- [M + H]⁺ pyrrol-1-yl-benzyl)-dihydro-1H-benzoimidazole-5- 505.4 piperidin-4-yl]-2-oxo- carboxylicacid allyl ester 2,3-dihydro-1H- dihydrochloride (intermediatebenzoimidazole-5- A2) and carboxylic acid 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (intermediate B14) 50 443.93 1-[1-(4-chloro-3-3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺ ethoxy-benzyl)-tetrahydro-quinoxaline-6- 444.3 piperidin-4-yl]-3-oxo- carboxylic acidallyl ester 1,2,3,4-tetrahydro- dihydrochloride (intermediatequinoxaline-6- A3) and carboxylic acid 4-chloro-3-ethoxy-benzaldehyde(intermediate B2) 51 475.49 1-[1-(4- 3-oxo-1-piperidin-4-yl-1,2,3,4-[M + H]⁺ difluoromethoxy-3- tetrahydro-quinoxaline-6- 476.3ethoxy-benzyl)- carboxylic acid allyl ester piperidin-4-yl]-3-oxo-dihydrochloride (intermediate 1,2,3,4-tetrahydro- A3) and quinoxaline-6-4-difluoromethoxy-3-ethoxy- carboxylic acid benzaldehyde (commerciallyavailable) 52 479.58 1-[1-(3-cyclopentyloxy-3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺ 4-methoxy-benzyl)-tetrahydro-quinoxaline-6- 480.4 piperidin-4-yl]-3-oxo- carboxylic acidallyl ester 1,2,3,4-tetrahydro- dihydrochloride (intermediatequinoxaline-6- A3) and carboxylic acid 3-cyclopentyloxy-4-methoxy-benzaldehyde (commercially available) 53 481.59 1-[1-(3,5-diisopropoxy-3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺ benzyl)-piperidin-4-yl]-tetrahydro-quinoxaline-6- 482.4 3-oxo-1,2,3,4- carboxylic acid allylester tetrahydro-quinoxaline- dihydrochloride (intermediate 6-carboxylicacid A3) and 3,5-diisopropoxy-benzaldehyde (intermediate B8) 54 525.601-[1-(3,5-diethoxy-4- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺ethoxycarbonyl- tetrahydro-quinoxaline-6- 526.4 benzyl)-piperidin-4-yl]-carboxylic acid allyl ester 3-oxo-1,2,3,4- dihydrochloride (intermediatetetrahydro-quinoxaline- A3) and 6-carboxylic acid2,6-diethoxy-4-formyl-benzoic acid ethyl ester (intermediate B9) 55471.53 1-[1-(3,5-diethoxy-4- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺fluoro-benzyl)- tetrahydro-quinoxaline-6- 472.2 piperidin-4-yl]-3-oxo-carboxylic acid allyl ester 1,2,3,4-tetrahydro- dihydrochloride(intermediate quinoxaline-6- A3) and carboxylic acid3,5-diethoxy-4-fluoro- benzaldehyde (intermediate B10) 56 487.981-[1-(4-chloro-3,5- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺diethoxy-benzyl)- tetrahydro-quinoxaline-6- 488.2 piperidin-4-yl]-3-oxo-carboxylic acid allyl ester 1,2,3,4-tetrahydro- dihydrochloride(intermediate quinoxaline-6- A3) and carboxylic acid4-chloro-3,5-diethoxy- benzaldehyde (intermediate B11) 57 532.441-[1-(4-bromo-3,5- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺diethoxy-benzyl)- tetrahydro-quinoxaline-6- 534.3 piperidin-4-yl]-3-oxo-carboxylic acid allyl ester 1,2,3,4-tetrahydro- dihydrochloride(intermediate quinoxaline-6- A3) and carboxylic acid4-bromo-3,5-diethoxy- benzaldehyde (intermediate B12) 58 518.611-[1-(3,5-diethoxy-4- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺pyrrol-1-yl-benzyl)- tetrahydro-quinoxaline-6- 519.4piperidin-4-yl]-3-oxo- carboxylic acid allyl ester 1,2,3,4-tetrahydro-dihydrochloride (intermediate quinoxaline-6- A3) and carboxylic acid3,5-diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate B14) 59 547.631-[1-(2,6-diethoxy-4′- 3-oxo-1-piperidin-4-yl-1,2,3,4- [M + H]⁺fluoro-biphenyl-4- tetrahydro-quinoxaline-6- 548.4ylmethyl)-piperidin-4- carboxylic acid allyl ester yl]-3-oxo-1,2,3,4-dihydrochloride (intermediate tetrahydro-quinoxaline- A3) and6-carboxylic acid 2,6-diethoxy-4′-fluoro-biphenyl- 4-carbaldehyde(intermediate B15) 60 398.44 1-[1-(3-ethoxy-4- 1-piperidin-4-yl-1H- [M +H]⁺ fluoro-benzyl- benzotriazole-5-carboxylic acid 399.3piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3-ethoxy-4-fluoro-benzaldehyde(intermediate B1) 61 414.89 1-[1-(4-chloro-3- 1-piperidin-4-yl-1H- [M +H]⁺ ethoxy-benzyl)- benzotriazole-5-carboxylic acid 415.3piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 4-chloro-3-ethoxy-benzaldehyde(intermediate B2) 62 396.45 1-[1-(3-ethoxy-4- 1-piperidin-4-yl-1H- [M +H]⁺ hydroxy-benzyl)- benzotriazole-5-carboxylic acid 397.2piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3-ethoxy-4-hydroxy- benzaldehyde(commercially available) 63 410.47 1-[1-(3-ethoxy-4-1-piperidin-4-yl-1H- [M + H]⁺ methoxy-benzyl)-benzotriazole-5-carboxylic acid 411.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-ethoxy-4-methoxy- benzaldehyde (commercially available) 64 424.501-[1-(3,4-diethoxy- 1-piperidin-4-yl-1H- [M + H]⁺benzyl)-piperidin-4-yl]- benzotriazole-5-carboxylic acid 425.31H-benzotriazole-5- allyl ester dihydrochloride carboxylic acid(intermediate A4) and 3,4-diethoxy-benzaldehyde (commercially available)65 436.51 1-[1-(4-allyloxy-3- 1-piperidin-4-yl-1H- [M + H]⁺ethoxy-benzyl)- benzotriazole-5-carboxylic acid 437.4piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 4-allyloxy-3-ethoxy- benzaldehyde(commercially available) 66 438.53 1-[1-(3-ethoxy-4-1-piperidin-4-yl-1H- [M + H]⁺ isopropoxy-benzyl)-benzotriazole-5-carboxylic acid 439.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 67 452.551-[1-(3-ethoxy-4- 1-piperidin-4-yl-1H- [M + H]⁺ isobutoxy-benzyl)-benzotriazole-5-carboxylic acid 453.4 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-ethoxy-4-isobutoxy- benzaldehyde (commercially available) 68 466.581-{1-[3-ethoxy-4-(1- 1-piperidin-4-yl-1H- [M + H]⁺ethyl-propoxy)-benzyl]- benzotriazole-5-carboxylic acid 467.4piperidin-4-yl}-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3-ethoxy-4-(1-ethyl-propoxy)-benzaldehyde (intermediate B3) 69 464.57 1-[1-(4-cyclopentyloxy-1-piperidin-4-yl-1H- [M + H]⁺ 3-ethoxy-benzyl)-benzotriazole-5-carboxylic acid 465.4 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid4-cyclopentyloxy-3-ethoxy- benzaldehyde (commercially available) 70486.57 1-[1-(4-benzyloxy-3- 1-piperidin-4-yl-1H- [M + H]⁺ethoxy-benzyl)- benzotriazole-5-carboxylic acid 487.4piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 4-benzyloxy-3-ethoxy- benzaldehyde(commercially available) 71 446.45 1-[1-(4- 1-piperidin-4-yl-1H- [M +H]⁺ difluoromethoxy-3- benzotriazole-5-carboxylic acid 447.3ethoxy-benzyl)- allyl ester dihydrochloride piperidin-4-yl]-1H-(intermediate A4) and benzotriazole-5- 4-difluoromethoxy-3-ethoxy-carboxylic acid benzaldehyde (commercially available) 72 424.501-[1-(4-methoxy-3- 1-piperidin-4-yl-1H- [M + H]⁺ propoxy-benzyl)-benzotriazole-5-carboxylic acid 425.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid4-methoxy-3-propoxy- benzaldehyde (intermediate B16) 73 424.501-[1-(3-isopropoxy-4- 1-piperidin-4-yl-1H- [M + H]⁺ methoxy-benzyl)-benzotriazole-5-carboxylic acid 425.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-isopropoxy-4-methoxy- benzaldehyde (commercially available) 74 422.481-[1-(3-allyloxy-4- 1-piperidin-4-yl-1H- [M + H]⁺ methoxy-benzyl)-benzotriazole-5-carboxylic acid 423.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-allyloxy-4-methoxy- benzaldehyde (intermediate B18) 75 420.471-[1-(4-methoxy-3- 1-piperidin-4-yl-1H- [M + H]⁺ prop-2-ynyloxy-benzotriazole-5-carboxylic acid 421.3 benzyl)-piperidin-4-yl]- allylester dihydrochloride 1H-benzotriazole-5- (intermediate A4) andcarboxylic acid 4-methoxy-3-prop-2-ynyloxy- benzaldehyde (commerciallyavailable) 76 438.53 1-[1-(3-butoxy-4- 1-piperidin-4-yl-1H- [M + H]⁺methoxy-benzyl)- benzotriazole-5-carboxylic acid 439.4piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3-butoxy-4-methoxy- benzaldehyde(intermediate B17) 77 438.53 1-[1-(3-isobutoxy-4- 1-piperidin-4-yl-1H-[M + H]⁺ methoxy-benzyl)- benzotriazole-5-carboxylic acid 439.3piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3-isobutoxy-4-methoxy-benzaldehyde (intermediate B5) 78 450.54 1-[1-(3-cyclopentyloxy-1-piperidin-4-yl-1H- [M + H]⁺ 4-methoxy-benzyl)-benzotriazole-5-carboxylic acid 451.4 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3-cyclopentyloxy-4-methoxy- benzaldehyde (commercially available) 79462.55 1-[1-(8-ethoxy-2,2- 1-piperidin-4-yl-1H- [M + H]⁺dimethyl-2H-chromen- benzotriazole-5-carboxylic acid 463.36-ylmethyl)-piperidin- allyl ester dihydrochloride4-yl]-1H-benzotriazole- (intermediate A4) and 5-carboxylic acid8-ethoxy-2,2-dimethyl-2H- chromene-6-carbaldehyde (intermediate B6) 80424.50 1-[1-(3,5-diethoxy- 1-piperidin-4-yl-1H- [M + H]⁺benzyl)-piperidin-4-yl]- benzotriazole-5-carboxylic acid 425.31H-benzotriazole-5- allyl ester dihydrochloride carboxylic acid(intermediate A4) and 3,5-diethoxy-benzaldehyde (intermediate B7) 81442.49 1-[1-(3,5-diethoxy-4- 1-piperidin-4-yl-1H- [M + H]⁺fluoro-benzyl)- benzotriazole-5-carboxylic acid 443.3piperidin-4-yl]-1H- allyl ester dihydrochloride benzotriazole-5-(intermediate A4) and carboxylic acid 3,5-diethoxy-4-fluoro-benzaldehyde (intermediate B10) 82 458.95 1-[1-(4-chloro-3,5-1-piperidin-4-yl-1H- [M + H]⁺ diethoxy-benzyl)-benzotriazole-5-carboxylic acid 459.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid4-chloro-3,5-diethoxy- benzaldehyde (intermediate B11) 83 503.401-[1-(4-bromo-3,5- 1-piperidin-4-yl-1H- [M + H]⁺ diethoxy-benzyl)-benzotriazole-5-carboxylic acid 505.3 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid4-bromo-3,5-diethoxy- benzaldehyde (intermediate B12) 84 489.581-[1-(3,5-diethoxy-4- 1-piperidin-4-yl-1H- [M + H]⁺ pyrrol-1-yl-benzyl)-benzotriazole-5-carboxylic acid 490.4 piperidin-4-yl]-1H- allyl esterdihydrochloride benzotriazole-5- (intermediate A4) and carboxylic acid3,5-diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate B14) 85 366.461-[1-(3-ethoxy-4- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ methyl-benzyl)-imidazo[4,5-c]pyridin-4-one 367.3 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one3-ethoxy-4-methyl- benzaldehyde (intermediate B19) 86 386.881-[1-(4-chloro-3- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ ethoxy-benzyl)-imidazo[4,5-c]pyridin-4-one 387.3 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one4-chloro-3-ethoxy-benzaldehyde (intermediate B2) 87 382.461-[1-(3-ethoxy-4- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺methoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 383.3 piperidin-4-yl]-1,5-dihydrochloride (intermediate dihydro-imidazo[4,5- A5) andc]pyridin-4-one 3-ethoxy-4-methoxy- benzaldehyde (commerciallyavailable) 88 410.52 1-[1-(3-ethoxy-4- 1-piperidin-4-yl-1,5-dihydro-[M + H]⁺ isopropoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 411.4piperidin-4-yl]-1,5- dihydrochloride (intermediate dihydro-imidazo[4,5-A5) and c]pyridin-4-one 3-ethoxy-4-isopropoxy- benzaldehyde(commercially available) 89 424.54 1-[1-(3-ethoxy-4-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ isobutoxy-benzyl)-imidazo[4,5-c]pyridin-4-one 425.3 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one3-ethoxy-4-isobutoxy- benzaldehyde (commercially available) 90 438.571-{1-[3-ethoxy-4-(1- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ethyl-propoxy)-benzyl]- imidazo[4,5-c]pyridin-4-one 439.4piperidin-4-yl}-1,5- dihydrochloride (intermediate dihydro-imidazo[4,5-A5) and c]pyridin-4-one 3-ethoxy-4-(1-ethyl-propoxy)- benzaldehyde(intermediate B3) 91 436.56 1-[1-(4-cyclopentyloxy-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ 3-ethoxy-benzyl)-imidazo[4,5-c]pyridin-4-one 437.4 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one4-cyclopentyloxy-3-ethoxy- benzaldehyde (commercially available) 92458.56 1-[1-(4-benzyloxy-3- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ethoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 459.4 piperidin-4-yl]-1,5-dihydrochloride (intermediate dihydro-imidazo[4,5- A5) andc]pyridin-4-one 4-benzyloxy-3-ethoxy- benzaldehyde (commerciallyavailable) 93 418.44 1-[1-(4- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺difluoromethoxy-3- imidazo[4,5-c]pyridin-4-one 419.2 ethoxy-benzyl)-dihydrochloride (intermediate piperidin-4-yl]-1,5- A5) anddihydro-imidazo[4,5- 4-difluoromethoxy-3-ethoxy- c]pyridin-4-onebenzaldehyde (commercially available) 94 410.52 1-[1-(3-isobutoxy-4-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ methoxy-benzyl)-imidazo[4,5-c]pyridin-4-one 411.4 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one3-isobutoxy-4-methoxy- benzaldehyde (intermediate B5) 95 422.531-[1-(3-cyclopentyloxy- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺4-methoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 423.2piperidin-4-yl]-1,5- dihydrochloride (intermediate dihydro-imidazo[4,5-A5) and c]pyridin-4-one 3-cyclopentyloxy-4-methoxy- benzaldehyde(commercially available) 96 434.54 1-[1-(8-ethoxy-2,2-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ dimethyl-2H-chromen-imidazo[4,5-c]pyridin-4-one 435.4 6-ylmethyl)-piperidin- dihydrochloride(intermediate 4-yl]-1,5-dihydro- A5) and imidazo[4,5-c]pyridin-8-ethoxy-2,2-dimethyl-2H- 4-one chromene-6-carbaldehyde (intermediateB6) 97 414.48 1-[1-(3,5-diethoxy-4- 1-piperidin-4-yl-1,5-dihydro- [M +H]⁺ fluoro-benzyl)- imidazo[4,5-c]pyridin-4-one 415.4piperidin-4-yl]-1,5- dihydrochloride (intermediate dihydro-imidazo[4,5-A5) and c]pyridin-4-one 3,5-diethoxy-4-fluoro- benzaldehyde(intermediate B10) 98 430.94 1-[1-(4-chloro-3,5-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ diethoxy-benzyl)-imidazo[4,5-c]pyridin-4-one 431.4 piperidin-4-yl]-1,5- dihydrochloride(intermediate dihydro-imidazo[4,5- A5) and c]pyridin-4-one4-chloro-3,5-diethoxy- benzaldehyde (intermediate B11) 99 475.391-[1-(4-bromo-3,5- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺diethoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 477.3 piperidin-4-yl]-1,5-dihydrochloride (intermediate dihydro-imidazo[4,5- A5) andc]pyridin-4-one 4-bromo-3,5-diethoxy- benzaldehyde (intermediate B12)100 411.51 1-[1-(4-amino-3,5- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺diethoxy-benzyl)- imidazo[4,5-c]pyridin-4-one 412.3 piperidin-4-yl]-1,5-dihydrochloride (intermediate dihydro-imidazo[4,5- A5) andc]pyridin-4-one 4-amino-3,5-diethoxy- benzaldehyde (intermediate B13)101 461.57 1-[1-(3,5-diethoxy-4- 1-piperidin-4-yl-1,5-dihydro- [M + H]⁺pyrrol-1-yl-benzyl)- imidazo[4,5-c]pyridin-4-one 462.4piperidin-4-yl]-1,5- dihydrochloride (intermediate dihydro-imidazo[4,5-A5) and c]pyridin-4-one 3,5-diethoxy-4-pyrrol-1-yl benzaldehyde(intermediate B14) 102 490.58 1-[1-(2,6-diethoxy-4′-1-piperidin-4-yl-1,5-dihydro- [M + H]⁺ fluoro-biphenyl-4-imidazo[4,5-c]pyridin-4-one 491.4 ylmethyl)-piperidin-4- dihydrochloride(intermediate yl]-1,5-dihydro- A5) and imidazo[4,5-c]pyridin-2,6-diethoxy-4′-fluoro-biphenyl- 4-one 4-carbaldehyde (intermediate B15)

Example 1032-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-oneStep 1: 4-(1-Oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 2-bromomethyl-benzoic acid methyl ester (1.50 g, 6.55mmol, 1.0 equiv; [CAS RN 2417-73-4]) in methanol (12.5 mL) andtriethylamine (1.10 mL) was added 4-amino-piperidine-1-carboxylic acidtert-butyl ester (1.38 g, 6.88 mmol, 1.05 equiv; commercially available)and the reaction stirred at rt overnight. The reaction mixture waspoured on crashed ice, extracted with ethyl acetate, the combinedorganic phases washed with water and a sat. solution of NaCl, dried overMgSO₄ and concentrated by evaporation under reduced pressure. The crudematerial was purified with silica column chromatography eluting withhexane/ethyl acetate (1:1) followed by crystallization from hexane/ethylacetate to obtain 1.12 g (54%) of the title compound as white crystals.MS (ISP): 261.0 [M-tert-Bu+H]⁺.

Step 2: 2-Piperidin-4-yl-2,3-dihydro-isoindol-1-one trifluoroacetate(Intermediate A6)

To a solution of4-(1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (0.50 g, 1.58 mmol) in dichloromethane (15 mL) wasadded trifluoro-acetic acid (3.0 mL) and the reaction mixture stirred atambient temperature during 4 h. The solvent was removed under reducedpressure and the crude product (0.710 g) used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the trifluoroacetate salt. MS (ISP): 217.4 [M+H]⁺.

Step 3:2-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one

To a solution of 2-piperidin-4-yl-2,3-dihydro-isoindol-1-onetrifluoroacetate (164.0 mg, 0.27 mmol, 1.0 equiv; 36% purity accordingto mass balance in preceeding step) in isopropanol (3.4 mL) was added3-ethoxy-4-methyl-benzaldehyde (44.8 mg, 0.27 mmol, 1.0 equiv;intermediate B19), titanium tetra-isopropoxide (232.8 mg, 0.82 mmol, 3.0equiv) and sodium cyanoborohydride (34.3 mg, 0.55 mmol, 2.0 equiv). Thereaction mixture was allowed to react overnight and then poured directlyonto a silica column. Eluting with ethyl acetate/triethylamine (98:2)yielded 29.0 mg (29%) of the title compound as white crystals. MS (ISP):365.1 [M+H]⁺.

The dihydro-isoindolone intermediate A7 was prepared as described below.Synthesis of Dihydro-isoindolone Intermediate A7 to be used in Table 2

Intermediate A7 5-Methoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-onetrifluoroacetate

Step 1: 2-Bromomethyl-4-methoxy-benzoic acid methyl ester

To a solution of 4-methoxy-2-methyl-benzoic acid methyl ester (1.47 g,8.16 mmol, 1.0 equiv; commercially available) in CCl₄ (15 mL) was addedN-bromosuccinimide (1.60 g, 8.97 mmol, 1.1 equiv) and dibenzoyl peroxide(0.198 g, 0.45 mmol, 0.05 equiv). The mixture was heated to reflux for1.5 h, when TLC indicated that still some starling material was left.Therefore, additional N-bromosuccinimide (0.16 g, 0.90 mmol, 0.11 equiv)and dibenzoyl peroxide (0.080 g, 0.41 mmol, 0.18 equiv) was added andheating continued for 1 h. The reaction mixture was cooled down, pouredon crashed ice, extracted with ethyl acetate, the combined organicphases washed with a sat. solution of NaCl, dried over Na₂SO₄ andconcentrated by evaporation under reduced pressure. The crude materialwas purified with silica column chromatography eluting with hexane/ethylacetate (95:5) affording 1.43 g (68%) of the title compound as yellowcrystals. ¹H NMR (300 MHz, CDCl₃): δ 3.87 (s, 3H), 3.91 (s, 3H), 4.97(s, 2H), 6.86 (dd, J=8.7 Hz, J=2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 7.99(d, J=8.7 Hz, 1H).

Step 2:4-(5-Methoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.28g, 4.94 mmol, 1.0 equiv) in methanol (9 mL) and triethylamine (0.83 mL)was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.04 g,5.19 mmol, 1.05 equiv; commercially available) and the reaction stirredat rt overnight. The reaction mixture was poured on crashed ice/dilutedHCl, extracted with ethyl acetate, the combined organic phases washedwith a sat. solution of NaHCO₃ and water, dried over Na₂SO₄ andconcentrated by evaporation under reduced pressure. The crude materialwas purified with silica column chromatography eluting with hexane/ethylacetate (3:7) yielding 0.84 g (49%) of the title compound as whitecrystals. MS (ISP): 347.3 [M+H]⁺.

Step 3: 5-Methoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-onetrifluoroacetate

To a solution of4-(5-methoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (0.84 g, 2.44 mmol) in dichloromethane (8.5 mL)was added trifluoro-acetic acid (1.7 mL) and the reaction mixturestirred at rt overnight. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thetrifluoroacetate salt. MS (ISP): 247.3 [M+H]⁺.

Examples 104 to 110

According to the procedure described for the synthesis of example103/step 3 further dihydro-isoindolone derivatives have been synthesizedfrom 2-piperidin-4-yl-2,3-dihydro-isoindol-1-one trifluoroacetate(intermediate A6) and5-methoxy-2piperidin-4yl-2,3-dihydro-isoindol-1-one trifluoroacetate(intermediate A7) and the respective benzaldehyde intermediate asindicated in Table 2. The results are compiled in Table 2 and compriseexample 104 to example 110.

TABLE 2 ISP No MW Compound Name Starting Materials [M + H]⁺ 104 422.572-[1-(3,5- 2-piperidin-4-yl-2,3-dihydro- [M + H]⁺ diisopropoxy-benzyl)-isoindol-1-one trifluoroacetate 423.2 piperidin-4-yl]-2,3- (intermediateA6) and dihydro-isoindol-1-one 3,5-diisopropoxy-benzaldehyde(intermediate B8) 105 412.50 2-[1-(3,5-diethoxy-4-2-piperidin-4-yl-2,3-dihydro- [M + H]⁺ fluoro-benzyl)- isoindol-1-onetrifluoroacetate 413.4 piperidin-4-yl]-2,3- (intermediate A6) anddihydro-isoindol-1-one 3,5-diethoxy-4-fluoro- benzaldehyde (intermediateB10) 106 444.55 2-[1-(2-ethoxy-4′- 2-piperidin-4-yl-2,3-dihydro- [M +H]⁺ fluoro-biphenyl-4- isoindol-1-one trifluoroacetate 445.2ylmethyl)-piperidin-4- (intermediate A6) and yl]-2,3-dihydro-2-ethoxy-4′-fluoro-biphenyl-4- isoindol-1-one carbaldehyde (intermediateB20) 107 452.59 2-[1-(3,5- 5-methoxy-2-piperidin-4-yl- [M + H]⁺diisopropoxy-benzyl)- 2,3-dihydro-isoindol-1-one 453.4piperidin-4-yl]-5- trifluoroacetate (intermediate A7)methoxy-2,3-dihydro- and isoindol-1-one 3,5-diisopropoxy-benzaldehyde(intermediate B8) 108 442.53 2-[1-(3,5-diethoxy-4-5-methoxy-2-piperidin-4-yl- [M + H]⁺ fluoro-benzyl)-2,3-dihydro-isoindol-1-one 443.1 piperidin-4-yl]-5- trifluoroacetate(intermediate methoxy-2,3-dihydro- A7) and isoindol-1-one3,5-diethoxy-4-fluoro- benzaldehyde (intermediate B10) 109 489.612-[1-(3,5-diethoxy-4- 5-methoxy-2-piperidin-4-yl- [M + H]⁺pyrrol-1-yl-benzyl)- 2,3-dihydro-isoindol-1-one 490.3 piperidin-4-yl]-5-trifluoroacetate (intermediate methoxy-2,3-dihydro- A7) andisoindol-1-one 3,5-diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediateB14) 110 474.57 2-[1-(2-ethoxy-4′- 5-methoxy-2-piperidin-4-yl- [M + H]⁺fluoro-biphenyl-4- 2,3-dihydro-isoindol-1-one 475.1ylmethyl)-piperidin-4- trifluoroacetate (intermediate yl]-5-methoxy-2,3-A7) and dihydro-isoindol-1-one 2-ethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate B20)

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcristallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120mg or 350 mg, respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following, ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I  25.0 mg Lactose 150.0 mgMaize starch  20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula I 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula I 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula I:

wherein A is —O— or —NH—; R¹ is selected from the group consisting ofC₂₋₇-alkyl, C₂₋₇-alkenyl, C₃₋₇-alkinyl, C₃₋₇-cycloalkyl,halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl and benzyl; R² is selectedfrom the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy,C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,—O-benzyl, —O—C₃₋₇-cycloalkyl, unsubstituted phenyl or phenylsubstituted by one to three groups independently selected fromC₁₋₇-alkyl, halogen and C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl,halogen-C₁₋₇-alkoxy, amino, pyrrolyl, imidazolyl and —C(O)OR⁴, whereinR⁴ is C₁₋₇-alkyl; R³ is hydrogen or C₁₋₇-alkoxy; or R² and R³ are bondedto each other to form a ring together with the carbon atoms they areattached to and R² and R³ together are —O—C(CH₃)₂—CH═CH—; G is selectedfrom the groups

wherein R⁵ is hydrogen or C₁₋₇-alkyl; R⁶, R⁷, R⁸ and R⁹ are —COOH; R¹⁰is hydrogen or C₁₋₇-alkoxy; and pharmaceutically acceptable saltsthereof.
 2. The compound according to claim 1, wherein A is O.
 3. Thecompound according to claim 1, wherein R¹ is selected from tile groupconsisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, C₃₋₇-alkinyl, C₃₋₇-cycloalkyland halogen-C₁₋₇-alkyl.
 4. The compound according to claim 1, wherein R²is selected from the group consisting of ethyl, propyl, isopropyl,allyl, 2-fluoroethyl, butyl, isobutyl, cyclopentyl and 2-propynyl. 5.The compound according to claim 1, wherein R² is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy,C₂₋₇-alkenyloxy, —O-benzyl, —O—C₃₋₇-cycloalkyl, unsubstituted phenyl orphenyl substituted by one to three groups independently selected fromC₁₋₇-alkyl, halogen and C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkoxy,amino, pyrrolyl, imidazolyl and —C(O)OR⁴, wherein R⁴ is C₁₋₇-alkyl. 6.The compound according to claim 1, wherein R² is selected from the groupconsisting of hydrogen, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkoxy,pyrrolyl, phenyl substituted by halogen and —C(O)OR⁴, wherein R⁴ isC₁₋₇-alkyl.
 7. The compound according to claim 1, wherein R² is halogen.8. The compound according to claim 1, wherein R⁴ is hydrogen orC₁₋₇-alkoxy.
 9. The compound according to claim 1, wherein R² and R³ arebonded to each other to form a ring together with the carbon atoms theyare attached to and R² and R³ together arc —O—C(CH₃)₂—CH═CH—.
 10. Thecompound according to claim 1, wherein G is

and wherein R⁵ is hydrogen or C₁₋₇-alkyl and R⁶ is —COOH.
 11. Thecompound according to claim 10, wherein R⁵ is methyl.
 12. The compoundaccording to claim 1, wherein G is

and wherein R⁷ is —COOH.
 13. The compound according to claim 1, whereinG is

and wherein R⁸ is —COOH.
 14. The compound according to claim 1, whereinG is

and wherein R⁹ is —COOH.
 15. The compound according to claim 1, whereinG is


16. The compound according to claim 1, wherein G is

and wherein R¹⁰ is hydrogen or C₁₋₇-alkoxy.
 17. The compound accordingto claim 16, wherein R¹⁰ is methoxy.
 18. The compound according to claim1, selected from the group consisting of1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-isopropoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1-H-benzoimidazole-5-carboxylicacid,1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-allyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzotriazole-5-carboxylicacid,1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-1-benzotriazole-5-carboxylicacid, 1-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylic acid,1-[1-(3-isopropoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-methoxy-3-prop-2-ynyloxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo4,5-c]pyridin-4-one,1-[1-(3-ethoxy-4isobutoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-cyclopentyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-benzyloxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,2-[1-(2-ethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2,3-dihydro-isoindol-1-one,2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,2-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,2-[1-(2-ethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,and pharmaceutically acceptable salts thereof.
 19. The compoundaccording to claim 1, selected from the group consisting of1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-ethoxycarbonyl-benzyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-2-methyl-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylicacid,1-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3-cyclopentyloxy-4-methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1H-benzotriazole-5-carboxylicacid,1-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,1-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-1,5-dihydro-imidazo[4,5-c]pyridin-4-one,2-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-5-methoxy-2,3-dihydro-isoindol-1-one,and pharmaceutically acceptable salts thereof.
 20. A process for themanufacture of compounds according to claim 1, comprising the steps of:a) reacting a piperidine of the formula

wherein G is as defined in claim 1, with an aldehyde of the formula

wherein A and R¹ to R³ are as defined in claim 1, by employing areducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively, b) alkylating apiperidine of the formula

wherein G is as defined in claim 1, with a compound of the formula

wherein A and R¹ to R³ are as defined in claim 1 and X is a leavinggroup, under basic conditions to obtain a compound or formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt; or, alternatively, c) reacting acompound of the general formula

wherein G is as defined in claim 1, with a compound of the formula

wherein A and R¹ to R³ are as defined in claim 1, in the presence of atrialkylphosphine and a diazo-compound to obtain a compound of theformula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt.
 21. A pharmaceutical composition,comprising a therapeutically effective amount of a compound according toclaim 1 as well as a pharmaceutically acceptable carrier and/oradjuvant.
 22. A method for the treatment and/or prevention of diseaseswhich are associated with the modulation of SST receptors subtype 5,comprising the step of administering a therapeutically effective amountof a compound according to claim 1 to a human being or animal in needthereof.